Optically active esters of 7-substituted 3,5-difunctionalized 6-heptenoic acids

ABSTRACT

The present invention provides optically active esters of 7-substituted 3,5-difunctionalized 6-heptenoic acids represented by the following formula: ##STR1## wherein R is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group or a substituted vinyl group; 
     Ar is a condensed aromatic group; 
     X 1  and Y 1  are not the same and each is a hydrogen atom or a hydroxyl group; and 
     X 2  and Y 2  are not the same and each is a hydrogen atom or a hydroxyl group or enantiomers thereof.

This is a division of application Ser. No. 07,748,076 , filed Aug. 21,1991 now U.S. Pat. No. 5,276,154.

BACKGROUND OF THE INVENTION

The present invention relates to optically active esters of7-substituted 3,5-difunctionalized 6-heptenoic acids including esters ofβ,δ-diketocarboxylic acids and reduced products thereof. The esters areuseful as intermediates for preparing therapeutical agents which inhibitHMG-CoA reductase and are potent for hypercholesterolemia.

For example, optically active esters of β,δ-syn-dihydroxycarboxylicacids according to the present invention represented by the followingformula (IV): ##STR2## wherein R is a substituted or unsubstitutedaromatic group, a substituted or unsubstituted heteroaromatic group or asubstituted vinyl group; and

Ar is a condensed aromatic group, or optically active enantio-esters ofβ,δ-syn-dihydroxycarboxylic acids represented by the following formula(V'): ##STR3## wherein R and Ar are the same as above, can be convertedinto 7-substituted (3R, 5S, 6E)-3,5-dihydroxy-6-hepten-5-olides havingan inhibitory activity of HMG-CoA reductase or their enantiomers byhydrolyzing the compounds (IV) or (V'), or their enantiomers, followedby lactonizing the resulting acids.

Furthermore, optically active esters of β,δ-syn-dihydroxycarboxylicacids of the formula (IV) or (V'), or their enantiomers can also beutilized for preparing an insect pheromone,endo-1,3-dimethyl-2,9-dioxabicyclo[3.3.1]nonane as described inTetrahedron Lett., 28, 4773 (1987); ibid., 21, 3013 (1980); J. Org.Chem., 54, 2238 (1989); Chem. Pharm. Bull., 37, 1078 (1989); and Helv.Chim. Acta., 72, 1284 (1989).

Optically active 7-substituted (3R, 5S,6E)-3,5-dihydroxy-6-hepten-1,5-olides having an inhibitory activity ofHMG-CoA reductase have been prepared via either of the followingprocesses:

(1) protecting (2S,4R)-4-hydroxy-6-methoxy-tetrahydropyran-2-carbaldehyde, followed bysubjecting the protected compound to the Wittig reaction, hydrolysis andoxidation, successively [J. Med. Chem., 33, 52 (1990)]; or

(2) obtaining a lower alkyl ester or aryl ester of 7-substituted (3R,5S, 6E)-3,5-dihydroxy-6-heptenoic acid, followed by hydrolyzing theester [for example, EP 319,847; EP 324,347; J. Med. Chem., 32, 2038(1989)].

In the above process (1), the source of the optical activity is sugarderivatives [Tetrahedron Lett., 31, 1869 (1990); ibid., 30, 6015 (1989);ibid., 26, 4995, 2947 (1985)], glutamic acid [J. Chem. Soc., Chem.Commun., 1988, 1417], or ascorbic acid [Tetrahedron Lett., 26, 2951(1985)], of which functional groups are suitably transformed so thatdesired precursors are attained. Although the sources are easilyavailable natural products and thus inexpensive, multi-step operationsare required for removing unnecessary functional groups and transformingthe carbon skeletons in order to obtain the desired precursors.Therefore, the process is less attractive.

The precursor of the above process (2) is often prepared as a racemicmixture. Therefore, the process requires optical resolution forobtaining the desired [3R, 5S] enantiomer with the expense of the other[3S, 5R] enantiomer [J. Med. Chem., 29, 159 (1986)]. Asymmetricsynthesis of the [3R, 5S] enantiomer is achieved by repeating asymmetricaldol condensation of a chiral acetic acid ester with an aldehyde twice[Tetrahedron Lett., 28, 1385 (1987) ], by converting a chiralβ-hydroxyester into a chiral δ-hydroxy- β-ketoester, followed bystereoselective syn-reduction [Tetrahedron Lett., 31, 2545 (1990);ibid., 30, 5115 (1989); Japanese Patent Application Laying Open (KOKAI)Nos. 199945/89, 213270/89; U.S. Pat. No. 4,855,481], or by asymmetricepoxydation of an allylic alcohol [Tetrahedron Lett., 28, 703, 291(1987)]. These methods, however, require inevitable multi-stepoperations for transforming the carbon skeletons and controlling thestereochemistry.

The optically active esters of β,δ-syn-dihydroxycarboxylic acid areimportant as precursors for preparing 7-substituted (3R, 5S,6E)-3,5-dihydroxy-6-hepten-1,5-olides andendo-1,3-dimethyl-2,9-dioxabicyclo[3.3.1]nonane as described above. Ashort-step synthesis of racemic lower alkyl esters ofβ,δ-syn-dihydroxycarboxylic acid has been reported which comprises astereoselective syn-reduction of the corresponding lower alkyl esters ofβ,δ-diketocarboxylic acid [Japanese Patent Application Laying Open(KOKAI) No. 165547/89]. However, the method is not applicable toasymmetric synthesis of the esters of β,δ-syn-dihydroxycarboxylic acid[Tetrahedron Lett., 29, 6467 (1988)]. This is due to the planarstructure of the molecules of the β,δ-diketocarboxylic acid esters andto the absence of the known reducing agent or catalyst which maydistinguish the Re face and the Si face of the two carbonyl groups.Accordingly, lower alkyl esters of 7-substituted β,δ-diketo-6-heptenoicacid are not attractive as precursors of desired 7-substituted (3R, 5S,6E)-3,5-dihydroxy-6-hepten-5olides and their enantiomers.

Thus, these known methods for preparing optically active heptenolidesrequire tedious multi-step operations and/or optical resolutions ofracemic compounds with losing undesired enantiomers.

As a result of the extensive studies, the present inventors have foundthat an ester of a β,δ-diketocarboxylic acid or aβ-hydroxy-δ-ketocarboxylic acid with a 2-exo-aryl-3-exo-hydroxybornaneis useful as a precursor of the optically active ester ofβ,δ-syn-dihydroxycarboxylic acid of the formula (IV) or (V') and thatthe latter compound is easily converted into the finally desiredlactone. The both enantiomers of 2-exo-aryl-3-exo-hydroxybornane areeasily obtainable from (+)- or (-)-camphor.

SUMMARY OF THE INVENTION

Specifically, the present invention provides an optically active esterwith 2-exo-aryl-3-exo-hydroxybornane represented by the followingformula (I): ##STR4## wherein R is a substituted or unsubstitutedaromatic group, a substituted or unsubstituted heteroaromatic group or asubstituted vinyl group;

Ar is a condensed aromatic group;

X¹ and y¹ are not the same and each is a hydrogen atom or a hydroxylgroup, or may be combined to represent an oxygen atom which forms acarbonyl group together with the carbon atom to which X¹ and y¹ areattached; and X² and y² are not the same and each is a hydrogen atom ora hydroxyl group, or may be combined to represent an oxygen atom whichforms a carbonyl group together with the carbon atom to which X² and y²are attached, or an enantiomer thereof.

The specific types of the above ester include: (i) an optically activeester of β,δ-diketocarboxylic acid represented by the following formula(II): ##STR5## wherein R is a substituted or unsubstituted aromaticgroup, a substituted or unsubstituted heteroaromatic group or asubstituted vinyl group; and

Ar is a condensed aromatic group, or an enantiomer thereof;

(ii) an optically active ester of β-hydroxy-δ-ketocarboxylic acidrepresented by the following formula (III): ##STR6## wherein R is asubstituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group or a substituted vinyl group; and

Ar is a condensed aromatic group, or an enantiomer thereof;

(iii) an optically active ester of β,δ-syn-dihydroxycarboxylic acidrepresented by the following formula (IV): ##STR7## wherein R is asubstituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group or a substituted vinyl group; and

Ar is a condensed aromatic group, or an enantiomer thereof;

(iv) an optically active enantio-ester of β,δ-syn-dihydroxycarboxylicacid represented by the following formula (V): ##STR8## wherein R is asubstituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group or a substituted vinyl group;

Ar is a condensed aromatic group, or an enantiomer thereof.

The invention also provides a process for preparing an optically activeester of β,δ-diketocarboxylic acid of the formula (II) or itsenantiomers, which comprises treating an optically active ester ofacetoacetic acid or its enantiomer represented by the following formula(VI): ##STR9## wherein Ar is the same as above, with one or more bases,followed by condensing resulting dianion with an N-methoxyamiderepresented by the following formula (VII): ##STR10## wherein R is thesame as above;

each of R¹ and R² is a straight or branched alkyl group of 1 to 4 carbonatoms.

The invention further provides a process for preparing an opticallyactive ester of β-hydroxy-δ-ketocarboxylic acid of the formula (III) orits enantiomer, which comprises stereoselectively reducing an opticallyactive ester of β,δ-diketocarboxylic acid of the formula (II) or itsenantiomers using an aluminium hydride compound represented by theformula: HAlR³ ₂ as reducing agent, where R³ is a straight or branchedalkyl group of 1 to 8 carbon atoms.

The present invention also provides a process for preparing an opticallyactive ester of β,δ-syn-dihydroxycarboxylic acid of the formula (IV) orits enantiomer, which comprise stereoselectively reducing an opticallyactive ester of β-hydroxy-δ-ketocarboxylic acid of the formula (III) orits enantiomer using sodium borohydride as reducing agent in thepresence of an organoboron compound represented by the formula: R⁴ ₂ BZ¹where R⁴ is a straight or branched alkyl group of 1 to 8 carbon atomsand Z¹ is a halogen atom or an alkoxy group having 1 to 8 carbon atoms.

The present invention still provides a process for preparing anoptically active ester of β,δ-syn-dihydroxycarboxylic acid of theformula (IV) or its enantiomer, which comprise stereoselectivelyreducing an optically active ester of β,δ-diketocarboxylic acid of theformula (II) or its enantiomer using sodium borohydride as reducingagent in the presence of an organoboron compound represented by theformula: R⁵ ₂ BZ² where R⁵ is a straight or branched alkyl group of 2 to8 carbon atoms and Z² is a halogen atom or an alkoxy group having 1 to 8carbon atoms.

The present invention still further provides a process for preparing anoptically active enantio-ester of β,δ-syn-dihydroxycarboxylic acid ofthe formula (V) or its enantiomer, which comprises stereoselectivelyreducing an optically active ester of β,δ-diketocarboxylic acid of theformula (II) or its enantiomer using sodium borohydride as reducingagent in the presence of an organoboron compound represented by theformula: Me₂ BZ³ where Z³ is a halogen atom or an alkoxy group having 1to 8 carbon atoms.

The optically active esters according to the invention are useful asprecursors for preparing 7-substituted (3R, 5S,6E)-3,5-dihydroxy-6-hepten-1,5-olides having an inhibitory activity ofHMG-CoA reductase and their enantiomers as well as a sex-attractantpheromone of beetles, endo-1,3-dimethyl-2,9-dioxabicyclo[3.3.1]nonane inhigh optical yields without requiring tedious and material-consumingoptical resolution.

Accordingly, the present invention also provides a use of the opticallyactive ester of β,δ-syn-dihydroxycarboxylic acid of the formula (IV) or(V), or enantiomer thereof as the precursor for preparing the7-substituted (3R, 5S, 6E)-3,5-dihydroxy-6-hepten-5-olide or theenantiomer thereof which comprises hydrolyzing the optically activeester, followed by lactonization.

DETAILED DESCRIPTION OF THE INVENTION

The compounds according to the present invention are represented by theabove formula (I), specifically formulae (II), (III), (IV) and (V), oras their enantiomers.

The aromatic group of R may have 6 to 18 carbon atoms in the aromaticring and optionally be condensed with one or more other aromatic ringssuch as benzene or naphthalene. The heteroaromatic group of R may befive- or six-membered and optionally be condensed with one or more otheraromatic rings or heteroaromatic rings such as benzene, naphthalene,pyridine, pyrimidine, pyrazine, pyrazole, or thiophene.

The examples of the substituents in the substituted aromatic orheteroaromatic group or the substituted vinyl group include alkyl groupshaving 1 to 6 carbon atoms; cycloalkyl groups having 3 to 8 carbonatoms; halogen atoms; alkoxy groups having 1 to 6 carbon atoms; phenylgroups optionally substituted with one or more alkyl groups having 1 to6 carbon atoms, halogen atoms, alkoxy groups having 1 to 6 carbon atomsand combination thereof.

The number of the substitution in the substituted aromatic orheteroaromatic group may be one to five, preferably one to three. Thatin the substituted vinyl group is one to three.

The examples of R in the above formulae include phenyl group;substituted phenyl groups such as 4-tolyl, 4-chlorophenyl,4-methoxyphenyl, 3,5-dichloro-6-(4-fluorophenyl)phenyl,2,4-dimethyl-6-(4-fluoro-3-methylphenyl) phenyl; substituted indolylgroups such as 3-(4-fluorophenyl)-1-isopropylindol-2-yl; substitutedpyridyl groups such as 4-phenyl-2-methylpyridin-3-yl,2-isopropyl-6-phenyl-4-(4-fluorophenyl)pyridin-3-yl,2,5-diisopropyl-4-(4-fluorophenyl)pyridin-3-yl,2,6-diisopropyl-4-(4-fluorophenyl)-5-benzyloxymethylpyridin-3-yl,6-cyclopropyl-4-(4-fluorophenyl)-1,3-dimethylpyrazolo[3,4-b]pyridin-5-yl,4-(4-fluorophenyl)-1,3-dimethyl-6-(1-methylethyl)pyrazolo[3,4-b]pyridin-5-yl,1-t-butyl-6-cyclopropyl-4-(4-fluorophenyl)-3-methylpyrazolo[3,4-b]pyridin-5-yl,1-t-butyl-6-cyclopropyl-4-(4-fluorophenyl)-3-phenylpyrazolo[3,4-b]pyridin-5-yl,6-cyclopropyl-4-(4-fluorophenyl)thieno[2,3-b]pyridin-5-yl,6-cyclopropyl-3-ethyl-4-(4-fluorophenyl)-2-methylthieno[2,3-b]pyridin-5-yl;substituted pyrimidyl groups such as6-isopropyl-2-phenyl-4-(4-fluorophenyl)pyrimidin-5-yl,6-methyl-2-phenyl-4-(4-fluorophenyl)pyrimidin-5-yl,2,4-dimethyl-6-(4-fluorophenyl)pyrimidin-5-yl; substituted quinolylgroups such as 3-isopropyl-1-(4-fluorophenyl)-4-oxoquinolin-2-yl,2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl,4-(4-fluorophenyl)-2-(1-methylethyl)quinolin-3-yl,6-chloro-2-(1-methylethyl)-4-phenylquinolin-3-yl,4-(4-fluorophenyl)-6-methyl-2-(1-methylethyl)quinolin-3-yl,2-cyclopropyl-4-(4-fluorophenyl)-8-methylquinolin-3-yl; substitutedpyrazolyl groups such as5-(4-fluorophenyl)-3-isopropyl-1-phenylpyrazol-4-yl; substitutedpyridazyl groups such as3,4-bis(4-fluorophenyl)-6-isopropylpyridazin-5-yl; substitutedimidazolyl groups such as4-isopropyl-2-phenyl-1-(4-fluorophenyl)-1H-imidazol-5-yl; substitutedpyrrolyl groups such as2-isopropyl-1-phenyl-4-(4-fluorophenyl)pyrrol-3-yl,1-isopropyl-3,4-bis(4-fluorophenyl)pyrrol-2,5-diyl; substitutedimidazolin-2-onyl groups such as4-(4-fluorophenyl)-1-methyl-3-phenylimidazolin-2-on-5-yl; substitutedvinyl groups such as 2,2-diphenylethenyl,1-isopropyl-2,2-bis(4-fluorophenyl)ethenyl,1-(1-methyl-1H-tetrazol-5-yl)-2,2-(4-fluorophenyl)ethenyl. Especially,2,4-dimethyl-6-(4-fluoro-3-methylphenyl)phenyl,2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl, and1-isopropyl-2,2-bis(4-fluorophenyl)ethenyl are preferable because of thehigh potential of the corresponding optically active lactones.

The example of Ar in the above formulae includes condensed aromaticgroups such as naphthyl group, anthryl group, and phenanthryl group.Especially, 1-naphthyl group, 2-naphthyl group, 1-anthryl group, and2-phenanthryl group are preferable because of effective face blocking inthe hydride reduction.

The optically active ester of β,δ-diketocarboxylic acid of the formula(II) or its enantiomer is prepared by condensing the optically activeester of acetoacetic acid or its enantiomer represented by the formula(VI) with the N-methoxyamide represented by the formula (VII).

The optically active ester of acetoacetic acid of the formula (VI) orits enantiomer is easily prepared by ester-exchange of methyl or ethylacetoacetate with an alcohol represented by the following formula(VIII): ##STR11##

wherein Ar is a condensed aromatic group, or the enantiomer; or bycontacting the alcohol of the formula (VIII) or the enantiomer withdiketene.

The enantiomer of the compound (VIII) where Ar is 1-naphthyl is obtainedfrom easily available (+)-camphor and 1-naphthylmagnesium bromide asreported in J. Org. Chem., 52, 28(1987). According to the sameprocedure, the alcohol of the formula (VIII) itself is also obtainablefrom (-)-camphor as shown in Referential Example 1.

The ester-exchange for preparing the optically active ester of theformula (VI) is successfully conducted by heating a mixture of theacetoacetate and the alcohol of the formula (VIII) or its enantiomer ina molar ratio of 1:1 to 1:5. Solvent can be optionally used and theexamples include benzene, toluene, xylene, and dioxane. The reactionconveniently proceeds at a temperature between room temperature and aboiling point of the solvent used. The reaction is further acceleratedby adding an amine-type base, e.g., 4-dimethylaminopyridine,4-(1-pyrrolidino)pyridine or pyridine, as a catalyst. The amount of thecatalyst to be added ranges from so-called catalytic amount to 1 molarequivalent.

The reaction of the alcohol of the formula (VIII) with diketene isconducted under the well-known conditions.

The N-methoxyamide of the formula (VII) is attainable according to aconventional method which comprises converting the correspondingcarboxylic acid into acid chloride followed by treating the chloridewith N,O-dialkylhydroxylamine such as N,O-dimethylhydroxylamine asdescribed in Japanese Patent Application Laying Open (KOKAI) No.165547/89.

The optically active ester of β,δ-diketocarboxylic acid of the formula(II) or its enantiomer is prepared by treating the above opticallyactive acetoacetate of the formula (VI) with one or more bases, followedby condensing resulting dianion with the N-methoxyamide of the formula(VII) according to a known method described in Japanese PatentApplication Laying Open (KOKAI) No. 165547/89. The examples of the basesinclude lithium diisopropylamide, sodium hexamethyldisilazide,butyllithium, s-butyllithium, and t-butyllithium, as well as combinationof sodium hydride and one of the above bases. Thus, the compound (VII)is treated with 0.9 to 1.3 molar equivalents of sodium hydride and 0.9to 1.3 molar equivalents of lithium diisopropylamide or butyllithium atpreferably -78° C. to room temperature to give corresponding dianion,which was then treated with 0.5 to 2 molar equivalents of theN-methoxyamide of the formula (VII) at -78° C. to room temperature. Inthese reactions, it is convenient to employ a solvent such as diethylether, tetrahydrofuran (THF), toluene, hexamethylphosphoric triamide,N,N'-dimethylpropyleneurea or combination thereof.

The stereoselective reduction of the optically active ester ofβ,δ-diketocarboxylic acid of the formula (II) or its enantiomer into theoptically active ester of β,δ-syn-dihydroxycarboxylic acid of theformula (IV) or its enantiomer is achieved by the action of sodiumborohydride in the presence of an organoboron compound represented bythe formula: R⁵ ₂ BZ² where R⁵ is a straight or branched alkyl group of2 to 8 carbon atoms and Z² is a halogen atom or an alkoxy group having 1to 8 carbon atoms. The examples of the organic boron compounds includediethylmethoxyborane, dibutylmethoxyborane, diisobutylmethoxyborane,diethylethoxyborane, diethylchloroborane, and diethylbromoborane. Thereaction can be conducted in a protic solvent such as methanol, ethanol,or isopropyl alcohol at a temperature between -100° C. and a boilingpoint of the solvent, preferably between -78° C. and room temperature.Optionally, other inert solvents such as THF, diethyl ether,dichloromethane, and toluene may be used as a mixture with methanol. Theamount of the organoboron compound to be used ranges from equimolar tofive molar equivalents, preferably 1.0 to 2.5 molar equivalents relativeto the substrate (II). The amount of sodium borohydride may be in therange of from equimolar to large excess, preferably from 1 to 6 molarequivalents in view of the cost, relative to the substrate (II).

The optically active enantio-ester of β,δ-syn-dihydroxycarboxylic acidof the formula (V) or its enantiomer is prepared by the action of sodiumborohydride in the presence of an organoboron compound represented bythe formula: Me₂ BZ³ where Z³ is a halogen atom or an alkoxy grouphaving 1 to 8 carbon atoms, following a procedure similar to the aboveselective reduction into the optically active ester ofβ,δ-syn-dihydrocarboxylic acid of the formula (IV) or its enantiomer.The preferable examples of the organic boron compounds includedimethylhaloboranes, especially dimethylbromoborane, anddimethylalkoxyborane such as dimethylethoxyborane. The reductionproceeds stepwise. In view of the enolization of the carbonyl group ofthe β,δ-diketocarboxylic acid ester of the formula (II), it isreasonable that the optically active ester ofβ,δ-syn-dihydroxycarboxylic acid of the formula (IV) or its enantiomeris formed via the optically active ester of hydroxyketocarboxylic acidof the formula (III) or its enantiomer, and the optically activeenantio-ester of β,δ-syn-dihydroxycarboxylic acid of the formula (V') orits enantiomer via the optically active enantio-ester ofhydroxyketocarboxylic acid represented by the following formula (III'):##STR12## wherein R and Ar are the same as above, or its enantiomer.

Alternatively, the optically active ester of β,δ-syn-dihydroxycarboxylicacid of the formula (IV) or its enantiomer is prepared by reducing theoptically active ester of β,δ-diketocarboxylic acid of the formula (II)or its enantiomer to form the optically active ester ofβ-hydroxy-δ-ketocarboxylic acid of the formula (III) or its enantiomer(first stereoselective reduction), followed by further reduction of theresulting β-hydroxy-δ-ketocarboxylic acid ester (second stereoselectivereduction).

The first reduction is effected by employing an organoaluminium compoundrepresented by the formula: HAlR³ ₂ as a reducing agent, wherein R³ isethyl, propyl, butyl, isobutyl, or octyl group. The amount of theorganoaluminium compound may range from 1.8 to 10 molar equivalents,preferably 2 to 3 molar equivalents in view of the cost, relative to thesubstrate (II). The reaction is conducted in an aprotic solvent such asdiethyl ether, THF, benzene, toluene, hexane or dichloromethane at atemperature of from -150° C. to the boiling point of the solvent used.The preferred reaction temperature may depend on the particularsubstrate and is preferably between -100° C. to room temperature.

The second reduction is achieved by the action of sodium borohydride inthe presence of an organoboron compound represented by the formula: R⁴ ₂BZ¹, where R⁴ is a straight or branched alkyl group of 1 to 8 carbonatoms and Z¹ is a halogen atom or an alkoxy group having 1 to 8 carbonatoms, under similar conditions as described above at the reduction ofthe ester of β,δ-diketocarboxylic acid of the formula (II) into the sameproduct (IV). The preferable amount of sodium borohydride ranges from1.0 to 6.0 molar equivalents.

EXAMPLES

The present invention is further illustrated in detail with reference tothe following examples. It should be understood that the presentinvention is not limited to those examples.

REFERENTIAL EXAMPLE 1 ##STR13##

A THF (100 ml) solution of 1-bromonaphthalene (46 ml, 0.335 mol) wasslowly added dropwise to a THF (200 ml) suspension of metallic magnesiumribbon (9.5 g, 0.39 mol) under argon atmosphere, and the whole wasstirred at room temperature for 1 hour and at refluxing temperature ofTHF for 1 hour.

The resulting THF solution of 1-naphthylmagnesium bromide was cooled toroom temperature. Then, a THF (200 ml) solution of (-)-camphor (50 g,0.328 mol) was added thereto, and the whole was heated under reflux for72 hours. The reaction was terminated by cooling with ice-water andadding saturated ammonium chloride aq solution. Then, the organic layerwas filtered off, and the solid residue was treated with 10%hydrochloric acid and extracted with diethyl ether. The combined organiclayer was dried over anhydrous magnesium sulfate and, after filtration,concentrated to give 121 g of a crude(1S)-2-(1-naphthyl)-1,7,7-trimethylbicyclo [2.2.1]-heptan-2-ol as anoil.

To the resulting crude product dissolved in pyridine (150 ml) was addedthionyl chloride (12 ml) rapidly under ice cooling, and the whole wasfurther stirred for 1.5 hours. Water (150 ml) was added thereto, and thereaction mixture was extracted with hexane (100 ml×3 times). The hexaneextract was washed successively with 10% hydrochloric acid, saturatedcopper sulfate aq solution, saturated sodium hydrogen carbonate aqsolution, and saturated sodium chloride aq solution, dried overanhydrous magnesium sulfate, and finally concentrated in vacuo. Removalof remaining camphor and naphthalene from the residue at 110° C. under0.1 Torr afforded 57.5 g (67% yield) of(1S)-2-(1-naphthyl)-1,7,7-trimethyl-2-bicyclo[2.2.1]heptene.

The olefin was dissolved in toluene (100 ml), and borandimethyl sulfidecomplex (24 g, 30 ml, 0.316 mol) was added thereto. The mixture wasrefluxed for 5 hours and stirred at room temperature overnight, thencooled to 0° C. Thereto were added dropwise 50% sodium hydroxide aqsolution (75 ml), ethanol (50 ml) and 30% hydrogen peroxide (60 ml),successively. After stirring at room temperature for 1 hour, the organiclayer was separated, and the aqueous layer was extracted withdichloromethane (50 ml×twice). The combined organic layer was dried overanhydrous magnesium sulfate and concentrated in vacuo. The resultingsolid residue was dissolved in hexane (150 ml), and the solution wasallowed to stand at -78° C. to afford 14.9 g (24% yield) of(4R)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-endo-ol aspale gray solids. R_(f) =0.17 (ethyl acetate:hexane=1:9) IR (KBr): 3600,3450, 2995, 2900, 1605, 1515, 1455, 1395, 1290, 1155, 1060, 1040, 800,780 cm⁻¹.

¹ H NMR (CDCl₃): δ=0.52 (s, 3H), 0.90 (s, 3H), 1.03 (s, 3H), 1.10-2.36(m, 5H), 3.36 (d, J=6 Hz, 1H), 5.00-5.26 (br, 1H), 7.30-8.17 (m, 7H).

A dichloromethane (30 ml) solution of the above alcohol (13.4 g, 48mmol) was added to a mixture of pyridinium chlorochromate (25.8 g, 120mmol), sodium acetate (15.7 g, 192 mmol) and dichloromethane (270 ml),and the whole was stirred at room temperature for 3 hours. After addingCelite (20 g), the mixture was filtered through a Celite layer (50 g) toremove insoluble substances. The Celite layer was washed with diethylether (50 ml×twice) and acetone (50 ml) successively, and the combinedfiltrate was dried over anhydrous magnesium sulfate and thenconcentrated in vacuo. The crude product was purified by columnchromatography (silica gel 120 g, ethyl acetate:hexane=5:95) to give12.8 g of(4R)-3-exo(1-naphthyl)-4,7,7-trimethyl-2-bicyclo[2.2.1]heptan-2-one assolids. Recrystallization from ethyl acetate-dichloromethane (5:1)afforded 10.8 g (81% yield) of pure product. mp=203°-205° C. R_(f) =0.25(ethyl acetate:hexane=5:95) [α]_(D) ²⁰ =-190.31° (c 0.44, CHCl₃) IR(KBr): 3000, 2970, 2895, 1745, 1600, 1495, 1460, 1400, 1380, 1300, 1160,1100, 800, 780 cm⁻¹.

¹ H NMR (CDCl₃): δ=0.80 (s, 3H), 0.96 (s, 3H), 1.13 (s, 3H), 1.53-2.46(m, 5H), 4.13 (s, 1H), 7.33-8.00 (m, 7H). MS:m/z (rel. intensity) 278(M⁺, 8), 181 (9), 169 (13), 168 (100), 165 (12), 140 (16), 137 (7), 109(6), 69 (5), 55 (8), 53 (5), 41 (30).

The resulting ketone (2.76 g, 10 mmol) dissolved in THF (5 ml) was addedslowly to lithium aluminium hydride (0.40 g, 10.5 mmol) suspended in THF(20 ml), and the whole was stirred at room temperature for 1 hour. Thereaction was quenched by cooling the mixture to 0° C. and by addingwater (0.5 ml), 10% sodium hydroxide aq solution (0.5 ml), and water (2ml), successively. After stirring at room temperature for 30 minutes,the mixture was filtered to remove insoluble substances. The residue waswashed with diethyl ether and acetone. The combined organic layer wasdried over anhydrous magnesium sulfate and then concentrated. Theresulting crude product (2.3 g) was purified by recrystallization fromethanol (8 ml)-water (1.5 ml) to give 1.75 g (63% yield) of(4R)-3-exo-(1-naphthyl)-4,7,7-trimethylbicyclo[2.2.1 ]heptan-2-exo-ol.mp=151°-152° C. R_(f) =0.36 (ethyl acetate:hexane= 1:9) [α]_(D) ²⁰=+179.88° (c 0.70, CHCl₃) IR (KBr): 3610, 3540, 2980, 2910, 1605, 1515,1490, 1460, 1400, 1100, 1065, 1045, 800 cm⁻¹.

¹ _(H) NMR (CDCl₃): δ=0.83-2.06 (br m, 5H), 1.00 (s, 3H), 1.23(s, 3H),1.40 (s, 3H), 3.95 (d, J=8 Hz, 1H), 4.48 (d, J=8 Hz, 1H), 7.36-8.37 (brm, 7H). MS:m/z (rel. intensity) 280 (M⁺, 6), 171 (13), 170 (100), 169(13), 165 (11), 142 (21), 141 (20), 41 (14).

REFERENTIAL EXAMPLE 2 ##STR14##

Methyl acetoacetate (1.51 g, 13.0 mmol) was added to a mixture of(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-ol(1.20 g, 4.3 mmol), 4-dimethylaminopyridine (0.24 g, 2.0 mmol) andtoluene (20 ml) under argon atmosphere, and the whole was heated underreflux for 36 hours After cooling to 0° C. the mixture was diluted withsaturated ammonium chloride aq solution and extracted with diethyl ether(100 ml). The ethereal layer was washed with water (30 ml) twice anddried over anhydrous magnesium sulfate. After concentration, theresulting crude product (2.60 g) was purified by a column chromatography(silica gel, ethyl acetate:hexane=1:9) to give 1.54 g (98% yield) of(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo [2.2.1 ]heptan-2-exo-ylacetoacetate as a colorless oil. R_(f) =0.24 (hexane:ethyl acetate=10:1)[α]_(D) ²⁰ =-132.8° (C 0.53, CHCl.sub. 3) ¹ H NMR (CDCl₃): δ=1.01 (s,3H), 1.25 (s, 3H), 1.28 (s, 3H), 1.4-2.1 (m, 8H), 2.60 (s, 2H), 4.10 (d,J=8.9 Hz, 1H), 5.61 (d, J=8.8 Hz, 1H), 7.3-8.04 (m, 7H). IR (neat):2970, 1755, 1725, 1555, 1400, 1245, 1035 cm⁻¹. MS:m/z (rel. intensity)364 (M⁺, trace), 282 (12), 171 (13), 170 (100), 169 (13), 168 (11), 165(11), 142 (35), 141 (23), 139 (10), 95 (12).

EXAMPLE 1 ##STR15##

The acetoacetate (1.46 g, 4.0 mmol) obtained in Referential Example 2was added at 0° C. to a THF (25 ml) suspension of sodium hydride (0.16g, content 60%, oil dispersion, 4 mmol), and the whole as stirred for 15minutes and then cooled to -15° C. Butyllithium (1.60M hexane solution,2.5 ml, 4.0 mmol) was slowly added thereto dropwise, and the mixture wasstirred at -15° C. for 20 minutes and ten cooled at -78° C. THF (1 ml)solution of N-methoxy-N-methylcinnamamide (0.76 g, 4.0 mmol) was slowlyadded thereto, and the whole as stirred at -78° C. for 1 hour and atroom temperature overnight. Then, dil. hydrochloric acid (ca. 1 ml) asadded to terminate the reaction, and the whole as diluted with ethylacetate (ca. 30 ml). The organic layer as washed with saturated sodiumchloride aq solution (ca. 10) and then dried over anhydrous magnesiumsulfate. Concentration of the organic layer afforded 1.89 g of a crudeproduct which as purified by column chromatography (silica gel,dichloromethane) to give 0.51 g (26% yield) of(4S)-4,7,7-triethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(E)-7-phenyl-3,5-dioxo-6-heptenoate. R_(f) =0.48(hexane:dichloromethane=1:1) [α]_(D) ²⁰ =-141.0° (c 1.90, CHCl₃)

^(H) NMR (CDCl₃): δ=1.00 (s, 3H), 1.21 (s, 3H), 1.29 (s, 3H), 1.42-1.60(m, 2H), 1.80-1.72 (m, 1H), 1.91-2.20 (m, 2H), 2.60 (d, J=15.0 Hz, 1H),2.66 (d, J=15.0 Hz, 1H), 4.06 (d, J=8.5 Hz, 1H), 4.78 (s, 1H), 5.56 (d,J=8.5 Hz, 1H), 6.24 (d, J=16.0 Hz, 1H), 7.73 (dd, J=15.5, 7.5 Hz, 1H),7.40-7.50 (m, 7H), 7.56 (dd, J=6.5, 1.0 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H),7.66 (d, J=8.5 Hz, 1H), 7.77 (dd, J=8.0, 1.0 Hz, 1H), 8.02 (d, J= 8.5Hz, 1H), 14.48 (br s, 1H). IR (CHCl₃): 3060, 2950, 1735, 1640, 1590,1320, 1160, 1120, 1020, 985 cm⁻¹. MS:m/z (rel. intensity) 494 (M⁺, 3),263 (5), 247 (6), 215 (19), 179 (13), 173 (49), 171 (16), 170 (100), 165(23), 152 (9), 142 (12), 141 (39), 131 (48), 121 (12), 115 (20), 103(32), 93 (23), 84 (22), 69 (26), 67 (14), 55 (25), 51 (15), 47 (13), 43(31).

These data shows that the diketoester exists in an enol form representedby the following formula: ##STR16##

EXAMPLE 2 ##STR17##

The optically active diketocarboxylic acid ester (66 mg, 0.134 mmol)obtained in Example 1 was dissolved in a solvent mixture of THF (1 ml)and methanol (0.25 ml). Then, diethylmethoxyborane (15 mg, 0.15 mmol)was added thereto at -78° C. under argon atmosphere. The mixture wasonce warmed to room temperature and then cooled again to -78° C. Theretowas added sodium borohydride (26 mg, 0.67 mmol). After stirring at -78°C. for 3 hours and at room temperature overnight, the mixture wastreated with acetic acid (3 ml) to terminate the reaction, diluted withethyl acetate (ca. 10 ml), washed with 5% sodium hydrogen carbonate aqsolution (ca. 10 ml) and then dried over anhydrous magnesium sulfate.The organic layer was concentrated in vacuo to give a crude product.Methanol (30 ml) was added to the product and then removed in vacuo.This operation was repeated 10 times to decompose and evaporateorganoboron compound. The resulting crude product (51 mg) was purifiedby thin layer chromatography (silica gel, ethyl acetate:hexane=3:7) togive 37 mg (57% yield) of(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(3S, 5R)-7-phenyl-3,5-dihydroxy-6-heptenoate. HPLC analysis (silica gel60) of the product showed that it was an isomeric mixture in a ratio of4.5:1. Main component was separated by liquid chromatography. R_(f)=0.27 (hexane:ethyl acetate=2:1) IR (CHCl₃): 3550, 2950, 1730, 1600,1395, 1250, 1180, 1085, 1015, 965, 785 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.01 (s, 3H), 1.26 (s, 3H), 1.33 (s, 3H), 0.84-2.18(br m, 11H), 3.07-3.13 (m, 1H), 4.08 (d, J =8.8 Hz, 1H), 4.13-4.18 (m,1H), 5.53 (s, J=8.8 Hz, 1H), 6.00 (dd, J=6.18, 15.9 Hz, 1H), 6.51 (d,J=15.9 Hz, 1H), 7.21-7.52 (m, 8H), 7.66 (d, J=7.4 Hz, 1H), 7.73 (d,J=8.2 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H). MS:m/z(rel. intensity) 498 (M⁺, weak), 480 (weak), 463 (weak), 264 (19), 263(79), 262 (13), 235 (34), 207 (32), 201 (21), 170 (100), 155 (39), 141(84), 131 (42), 115 (33), 104 (16), 95 (19), 91 (33), 71 (28), 55 (24),43 (27).

REFERENTIAL EXAMPLE 3 ##STR18##

Aqueous 1M sodium hydroxide solution (60 μ1, 0.06 mmol) was added to amethanol (0.5 ml) solution of the dihydroxyester (18 mg, 0.036 mmol)obtained in Example 2. The mixture was stirred at room temperature for36 hours, diluted with water, and extracted with diethyl ether to removeneutral substances. The aqueous layer was acidified by adding 5Mhydrochloric acid and then extracted with diethyl ether (10 ml×3 times).The ethereal layer was washed with saturated sodium chloride aq solutionand then dried over anhydrous magnesium sulfate. The organic layer wasconcentrated in vacuo to give 8 mg of a corresponding carboxylic acidwhich was subsequently dissolved in toluene (2 ml). The solution washeated under reflux for 9 hours under argon atmosphere. After removingthe toluene in vacuo, the residue was purified by thin layerchromatography to give 6.1 mg (76% yield) of (3S,5R)-3,5-dihydroxy-7-phenyl-6-hepten-1,5-olide. HPLC analysis (CHIRAL OA,hexane:isopropyl alcohol=9:1) of the product showed that its opticalpurity was 94% ee. R_(f) =0.24 (dichloromethane:acetone=9:1) [α]_(D) ²⁰=-11.33° (c 0.41, CHCl₃)

¹ H NMR (CDCl₃): δ=1.94-2.01 (m, 1H), 2.09-2.15 (m, 1H), 2.65-2.71 (m,1H), 2.81 (dd, J=5.0, 17.8 Hz, 1H), 4.45 (quint, J=3.9 Hz, 1H), 5.37(dddd, J=1.1, 3.5, 6.0, 11.0 Hz, 1H), 6.21 (dd, J=6.0, 15.9 Hz, 1H),6.71 (dd, J=0.9, 15.9 Hz, 1H), 7.24-7.45 (m, 5H). MS:m/z (rel.intensity) 218 (M⁺, 15), 200 (13), 172 (10), 131 (21), 130 (20), 129(24), 114 (21), 104 (100), 91 (40), 77 (21), 68 (34), 51 (15), 43 (32).IR (KBr): 3440, 3080, 3050, 2975, 2940, 1725, 1600, 1500 1425, 1395,1375, 1245, 1165, 1075, 1035, 980, 755, 695 cm⁻¹ .

EXAMPLE 3 ##STR19##

The β,δ-diketocarboxylic acid ester (33 mg, 0.067 mmol) obtained inExample 1 was dissolved in THF (1 ml). Diisobutylaluminium hydride(DIBAL) (0.97M toluene solution, 0.153 ml, 0.148 mmol) was added theretoat -78° C. under argon atmosphere, and the whole was stirred at -78° C.for 4 hours. To the mixture was added 1M hydrochloric acid to terminatethe reaction and hydrolize the aluminium alkoxides at the same time. Theresulting mixture was extracted with ethyl acetate (50 ml), and theorganic layer was washed with 5% sodium hydrogen carbonate aq solution,dried over anhydrous magnesium sulfate and then concentrated in vacuo.The crude product (34 mg) was purified by thin layer chromatography(silica gel, ethyl acetate:hexane=4:6) to give 28 mg (85% yield) of(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(3S, 6E)-3-hydroxy-5-oxo-7-phenyl-6-heptenoate. HPLC analysis (silicagel 60, hexane:ethanol=80:1) of the product showed that it was anisomeric mixture in a ratio of 95.3:4.7. R_(f) =0.49 (hexane:ethylacetate=2:1) [C]_(D) ²⁰ =-99.17° (C 1.45, CHCl₃)

¹ H NMR (CDCl₃): δ=1.00 (s, 3H), 1.25 (s, 3H), 1.35 (s, 3H), 1.54-2.17(m, 10H), 3.54-3.61 (m, 1H), 4.09 (d, J= 8.7 Hz, 1H), 5.56 (d, J=8.7 Hz,1H), 6.53 (J=16 Hz, 1H), 7.37-7.6 (m, 13H). IR (CHCl₃): 3580, 2950,2925, 1725, 1680, 1650, 1605, 1390, 1120, 1090, 780 cm⁻¹. MS:m/z (rel.intensity) 496 (M⁺, 1), 478 (2), 350 (8), 262 (12), 240 (26), 199 (17),179 (10), 171 (14), 170 (100), 169 (10), 165 (16), 146 (17), 145 (12),141 (28), 131 (53), 103 (27), 77 (19), 71 (14), 55 (10), 43 (28).

EXAMPLE 4 ##STR20##

The β-hydroxy-δ-ketocarboxylic acid ester (15 mg, 0.03 mmol) obtained inExample 3 was dissolved in a solvent mixture of THF (0.5 ml) andmethanol (0.1 ml). Diethylmethoxyborane (4.3 μl , 0.031 mmol) was addedthereto at -78° C. under argon atmosphere. The mixture was stirred atroom temperature for 15 minutes and cooled again at -78° C. Sodiumborohydride (3.8 mg, 0.10 mmol) was added thereto. The mixture wasstirred at -78° C. for 7 hours and at room temperature for 8 hours,treated with acetic acid (1 ml), diluted with ethyl acetate, and washedsuccessively with 5% sodium hydrogen carbonate aq solution and saturatedsodium chloride aq solution. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated in vacuo to give 16 mg of acrude product. The crude product was purified by thin layerchromatography to give 12 mg (80% yield) of(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(3S, 5R, 6E)-7-phenyl-3,5-dihydroxy-6-heptenoate. HPLC analysis (silicagel 60, hexane:ethanol=40:1) of the product confirmed that it wascomposed of a single component. The spectral data of the product wereidentical with those of the main product obtained in Example 2. R_(f)=0.28 (hexane:ethyl acetate=2:1) [α]_(D) ²⁰ =-86.5° (c 0.55, CHCl₃)

REFERENTIAL EXAMPLE 4 ##STR21##

In a way similar to Referential Example 2, an acetoacetate,(4R)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-ylacetoacetate was prepared from(4R)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-olobtained in Referential Example 1, in 81% yield. R_(f) =0.25(hexane:ethyl acetate=10:1) [α]_(D) ²⁰ =+130.55° (c 0.80, CHCl₃)

The other spectral data of the product were identical with those of theproduct obtained in Referential Example 2.

EXAMPLE 5 ##STR22##

Following the procedure of Example 1,(4R)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl7-phenyl-3,5-dioxo-6-heptenoate was prepared from the optically activeacetoacetate obtained in Referential Example 4, in 26% yield. R_(f)=0.47 (hexane:dichloromethane=1:1) [α]_(D) ²⁰ =+102.35° (c 0.68, CHCl₃)

The other spectral data of the product were identical with those of theproduct obtained in Example 1.

EXAMPLE 6 ##STR23##

DIBAL (0.97M toluene solution, 0.113 ml, 0.11 mmol) was added at -78° C.under argon atmosphere to a THF (1 ml) solution of the optically activeβ,δ-diketocarboxylic acid ester (25 mg, 0.05 mmol) obtained in Example5, and the whole was stirred at -78° C. for 4 hours. Workup andpurification similar to those in Example 3 afforded 17.6 mg (70% yield)of (4R)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(3R, 6E)-3-hydroxy-5-oxo-7-phenyl-6-heptenoate. R_(f) =0.49(hexane:ethyl acetate=2:1) [α]_(D) ²⁰ =+103.7° (c 0.96, CHCl₃)

HPLC analysis (silica gel 60) of the product showed a diastereomericratio of >95:5. The other spectral data of the product were identicalwith those of the product obtained in Example 3.

EXAMPLE 7 ##STR24##

The optically active β-hydroxy-δ-ketocarboxylic acid ester (10 mg, 0.02mmol) obtained in Example 6 was dissolved in a mixture of THF (1 ml) andmethanol (0.1 ml). Then, diethylmethoxyborane (4 μl , 0.03 mmol) wasadded thereto at -78° C. under argon atmosphere. The mixture was stirredat room temperature for 15 minutes and cooled again at -78° C. Sodiumborohydride (4 mg, 0.11 mmol) was added thereto, and the whole wasstirred at -78° C. for 3 hours and at room temperature for 10 hours.Workup and purification afforded 7.8 mg (78% yield) of(4R)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(3R,5S,6E)-3,5-dihydroxy-7-phenyl-6-heptenoate. HPLC analysis (silicagel 60) of the product confirmed that it was composed of a singlecomponent. R_(f) =0.29 (hexane:ethyl acetate=2:1) [α] _(D) ²⁰ =+84.54°(c 0.44, CHCl₃)

The other spectral data of the product were identical with those of theproduct obtained in Example 4.

REFERENTIAL EXAMPLE 5 ##STR25##

Aqueous 1M sodium hydroxide solution (60 μl, 0.06 mmol) was added to amethanol (2 ml) solution of the optically activeβ,δ-syn-dihydroxycarboxylic acid ester (8 mg, 0.016 mmol) obtained inExample 7 and the whole was stirred at room temperature for 51 hours.Workup and purification similar to those in Referential Example 3afforded 2 mg (56% yield) of (3R,5S)-3,5-dihydroxy-7-phenyl-6-hepten-1,5-olide. R_(f) =0.24(dichloromethane:acetone=10:1) [α]_(D) ²⁰ =+10.66° (c 0.15, CHCl₃)

HPLC analysis (CHIRAL OA, hexane:isopropyl alcohol=9:1) of the productshowed that its diastereomer ratio was ca. 99:1 and the optical puritywas at least 97% ee. The spectral data of the product were completelyidentical with those of the product obtained in Referential Example 3.

REFERENTIAL EXAMPLE 6 ##STR26##

A THF (2.0 ml) solution of triethyl phosphonoacetate (EtO)₂ P(O)CH₂COOEt (0.224 g, 0.198 ml, 1.00 mmol) was added at 0° C. under argonatmosphere to sodium hydride (content 60%, oil dispersion, 42 mg, 1.04mmol) which had been washed with hexane, and the mixture was stirred for30 minutes. To the mixture was added a THF (1 ml) solution of3-methyl-2-bis(4-fluorophenyl)-methylidenbutanal (0.286 g, 1.0 mmol)prepared according to the method described in Tetrahedron Lett., 29, 929(1988). After stirring at room temperature overnight, the mixture wasthen diluted with water (25 ml) and extracted with hexane (30 ml×3times). The organic layer was washed with water (30 ml×twice) andsaturated sodium chloride aq solution and finally dried over anhydrousmagnesium sulfate. Concentration in vacuo followed by purification bythin layer chromatography (silica gel, ethyl acetate:hexane=1:9) to give0.28 g (79% yield) of ethyl(E)-5-methyl-4-bis(4-fluorophenyl)methylidene-2-hexenoate. mp=66°-67° C.R_(f) =0.49 (ethyl acetate:hexane=1:10) IR (KBr): 3075, 3050, 3005,1715, 1620, 1505, 1370, 1305, 1230, 1195, 1160, 1100, 1090, 1005, 875,855, 840, 780, 585, 565 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.28 (d, J=7.5 Hz, 6H), 1.37 (t, J=8.0 Hz, 3H),3.07-3.50 (m, 1H), 4.58 (q, J=8.0 Hz, 2H), 6.63 (d, J=18.0 Hz, 1H),7.36-8.03 (m, 8H), 8.08 (d, J=18.0 Hz, 1H). MS:m/z (rel. intensity) 356(M⁺, 35), 283 (17), 282 (27), 268 (15), 267 (61), 256 (13), 252 (17),251 (19), 208 (16), 241 (84), 240 (10), 239 (13), 238 (15), 227 (14),221 (16), 220 (13), 203 (29), 201 (20 ), 153 (21), 133 (15), 125 (16),123 (26), 109 (42), 43 (100).

A toluene (8 ml) solution of the above ester (2.38 g, 6.7 mmol) wasadded to powdery sodium hydroxide (0.34 g, 8.5 mmol) under argonatmosphere, and the whole was stirred at 60° C. for 5 hours. Thereaction mixture was neutralized with 1M hydrochloric acid (10 ml) andextracted with ethyl acetate (25 ml×3 times). The organic layer waswashed with water, saturated sodium chloride aq solution and then driedover anhydrous magnesium sulfate. Concentration of the organic layer invacuo followed by recrystallization from a mixed solvent (hexane:ethylacetate=4:1) gave 1.70 g (78% yield) of(E)-5-methyl-4-bis(4-fluorophenyl)methylidene-2-hexenoic acid.mp=225°-230° C. R_(f) =0.52 (hexane:ethyl acetate=1:1) IR (KBr): 3350,2400, 3025, 1690, 1615, 1515, 1430, 1320, 1225, 1165, 1100, 1080, 1005,965, 860, 850, 595, 580 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.20 (d, J=7.5 Hz, 6H), 2.73-3.20 (m, 1H), 6.03 (d,J=16.5 Hz, 1H), 6.73-7.36 (m, 8H), 7.45 (d, J=16.5 Hz, 1H). MS:m/z rel.intensity) 329 (M⁺ +1, 15), 328 (M⁺, 68), 313 (34), 285 (23), 268 (20),267 (82), 256 (43), 253 (18), 252 (27), 251 (30), 242 (19), 241 (98),239 (23), 238 (27), 227 (21), 221 (25), 220 (21), 214 (13), 203 (48),201 (42), 183 (17), 175 (20), 147 (20), 146 (19), 133 (31), 125 (27),123 (46), 109 (74), 45 (17), 43 (100).

To the above carboxylic acid (1.70 g, 5.2 mmol) dissolved in benzene (15ml) was added under argon atmosphere oxalyl chloride (1.27 g, 0.87 ml,10.0 mmol) distilled right before use. After stirring at 60° C. for 2hours, the solvent and excess oxalyl chloride were removed byevaporation at 60° C. under 20 Torr. To the residue dissolved indichloromethane (25 ml) were added N,O-dimethoxyhydroxylaminehydrochloride (0.52 g, 5.34 mmol) and pyridine (0.85 g, 0.86 ml, 10.7mmol), and the whole was stirred at room temperature overnight. Themixture was diluted with diethyl ether (100 ml), and the organic layerwas washed with saturated ammonium chloride aq solution (100 ml×twice),dried over anhydrous magnesium sulfate, and concentrated in vacuo. Theresulting crude product was purified by column chromatography (silicagel, ethyl acetate:hexane=3:7) to give 1.62 g (82% yield) ofN-methyl-N-methoxy-(E)-5-methyl-4-bis(4-fluorophenyl)methylidene-2-hexenamide. mp=109° -110° C. R_(f) =0.48(hexane:ethyl acetate=2:1) IR (KBr): 3200, 3005, 2960, 1660, 1610, 1515,1420, 1390, 1235, 1170, 1105, 1070, 1005, 865, 850, 810, 590, 575 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.21 (d, J=7.5 Hz, 6H), 2.65-3.20 (m, 1H), 3.20 (s,3H), 3.51 (s, 3H), 6.48 (d, J=16.5 Hz, 1H), 6.77-7.33 (m, 8H), 7.39 (d,J=16.5 Hz, 1H). MS:m/z (rel. intensity) 371 (M⁺, 11), 312(22), 311(100), 269 (14), 215 (22), 203 (14), 197 (14), 149 (16), 137 (18), 123(26), 109 (57), 55 (16), 43 (48).

EXAMPLE 8 ##STR27##

Sodium hydride (content 60%, oil dispersion, 104 mg, 2.5 mmol) waswashed with hexane and suspended in THF under argon atmosphere. To thesuspension was added at 0° C. a THF (2 ml) solution of the acetoacetate(0.91 g, 2.5 mmol) obtained in Referential Example 2, and the whole wasstirred at 0° C. for 0.5 hours. The mixture was cooled at -10° C., andthereto was added butyllithium (1.52M hexane solution, 1.62 ml, 2.5mmol) dropwise. The whole was stirred at -10° C. for 0.5 hours. Theresulting dianion was treated with a THF (2 ml) solution of the amide(0.93 g, 2.5 mmol) obtained in Referential Example 6. After stirring at-10° C. for 2 hours and at room temperature overnight, the mixture wascooled to 0° C., treated with 1M hydrochloric acid (6 ml) to terminatethe reaction and diluted with ethyl acetate (50 ml). The organic layerwas washed with 5M sodium hydrogen carbonate aq solution (3 ml) andsaturated sodium chloride aq solution and then dried over anhydrousmagnesium sulfate. Removal of the solvent in vacuo afforded 1.91 g of acrude product which was purified by column chromatography to give 0.66 g(38% yield) of(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(E)-9-methyl-8-bis(4-fluorophenyl)methylidene-3,5-dioxo-6-decenoate and0.38 g (42%) of the starting acetoacetate recovered. The yield of thedesired product was calculated to be 67% based on the starting materialconsumed. R_(f) =0.27 (hexane:dichloromethane=1:1) [α]_(D) ²⁰ =-116.230°(c 0.85, CHCl₃) IR (KBr): 3060, 2980, 2900, 1735, 1605, 1505, 1395,1320, 1225, 1160, 1095, 1015, 835, 785 cm⁻¹.

¹ H NMR (CDCl₃): δ=0.76-2.13 (m, 11H), 1.00 (s, 3H), 1.33 (s, 3H), 1.37(s, 3H), 2.53 (s, 2H), 2.84-3.24 (m, 1H), 4.08 (d, J=9 Hz, 1H), 4.75 (s,1H), 5.57 (d, J=9 Hz, 1H), 5.92 (d, J=16.5 Hz, 1H), 6.73-8.10 (m, 16H).MS:m/z (rel. intensity) 674 (M⁺, 2), 412 (4), 394 (13), 263 (14), 207(11), 203 (14), 171 (14), 170 (100), 169 (14), 165 (13), 142 (20), 141(26), 111 (28), 109 (12), 69 (27 ), 43 (22).

EXAMPLE 9 ##STR28##

The β,δ-diketocarboxylic acid ester (67 mg, 0.1 mmol) obtained inExample 8 was dissolved in a solvent mixture of THF (1 ml) and methanol(0.25 ml). Diethylmethoxyborane (11 mg, 15 μl, 0.11 mmol) was then addedat -78° C. under argon atmosphere. The mixture was stirred at roomtemperature for 10 minutes and then cooled again at -78° C. Sodiumborohydride (19 mg, 0.5 mmol) was added thereto, and the whole wasstirred at -78° C. for 3 hours. The mixture was warmed gradually to roomtemperature and stirred overnight. Then, acetic acid (2 ml) was addedthereto, and the whole was stirred for 10 minutes to terminate thereaction, diluted with water (10 ml), and extracted with ethyl acetate(20 ml×twice). The organic layer was washed with 5M sodium hydrogencarbonate aq solution and saturated sodium chloride aq solution and thendried over anhydrous magnesium sulfate. The organic layer wasconcentrated in vacuo to give a crude product. Methanol was added to theproduct and was then removed under heating. This operation was repeated6 times to decompose the boron chelates formed. The residue was purifiedby thin layer chromatography (silica gel, ethyl acetate:hexane=3:7) togive 56 mg (83% yield) of(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(3S, 5R,6E)-3,5-dihydroxy-9-methyl-8-bis(4-fluorophenyl)methylidene-6-decenoate.R_(f) =0.39 (hexane:ethyl acetate=2:1) [α]_(D) ²⁰ =-93.32° (c 5.00,CHCl₃) IR (CHCl₃): 3575, 2960, 2875, 1725, 1600, 1500, 1465, 1400, 1175,1090, 1010, 1000, 835 cm⁻¹.

¹ H NMR (CDCl₃): δ=0.79-0.98 (m, 2H), 1.00 (s, 3H), 1.05 (d, J =5.8 Hz,3H), 1.07 (d, J=5.8 Hz, 3H), 1.26 (s, 3H), 1.32 (s, 3H), 1.45-1.54 (m,1H), 1.56 (br s, 1H, OH), 1.59-1.63 (m, 2H), 1.72-1.85 (m, 2H),1.92-2.00 (m, 2H), 2.77-2.85 (m, 1H), 2.94-2.99 (m, 1H), 3.82-3.86 (m,1H), 4.08 (d, J=8.8 Hz, 1H), 5.38 (dd, J=6.35, 16.2 Hz, 1H), 5.51 (d,J=8.8 Hz, 1H), 6.04 (dd, J=1.1, 16.2 Hz, 1H) 6.86 (m, 8H), 7.38-8.05 (m,7H). MS:m/z (rel. intensity) 679 (M⁺, trace), 269 (13), 264 (22), 263(100), 207 (44), 170 (22), 141 (39), 109 (20).

REFERENTIAL EXAMPLE 7 ##STR29##

Aqueous 1M sodium hydroxide solution (0.15 ml, 0.15 mmol) was added to amethanol (1 ml) solution of the β,δ-syn-dihydroxycarboxylic acid ester(49 mg, 0.07 mmol) obtained in Example 9, and the whole was stirred atroom temperature for 61 hours. After the mixture was diluted with water(10 ml) and extracted with diethyl ether (10 ml×twice) to remove neutralsubstances, the aqueous layer was neutralized with cold 1M hydrochloricacid (0.5 ml) and extracted with diethyl ether (10 ml×3 times). Theethereal layer was washed with saturated sodium chloride aq solution,dried over anhydrous magnesium sulfate, and concentrated in vacuo. Theresulting crude carboxylic acid was dissolved in toluene (3 ml), and thesolution was heated under reflux at 110° C. for 5 hours under argonatmosphere. After removing the toluene in vacuo, the residue waspurified by thin layer chromatography to give 18 mg (63% yield) of (3S,5R,6E)-3,5-dihydroxy-9-methyl-8-bis(4-fluorophenyl)methylidene-6-decen-1,5-olide.R_(f) =0.63 (dichloromethane:acetone=10:1) [α]_(D) ²⁰ -91.03° (C 0.36,CHCl₃)

HPLC analysis (CHIRAL AD column, hexane:isopropyl alcohol=40:1) of theproduct showed that a trans:cis ratio was 83:17, enantiomer excess ofthe trans-isomer being 66% ee. The trans-isomer was separated by liquidchromatography. IR (CHCl₃): 3650, 2940, 2875, 1735, 1605, 1505, 1405,1365, 1260, 1235, 1160, 1130, 1095, 1060, 1040, 970, 835, 800 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.09 (d, J=5.4 Hz, 3H), 1.11 (d, J=5.4 Hz, 3H),1.46-1.65 (m, 1H), 1.75-1.81 (m, 1H), 2.54-2.61 (m, 1H), 2.70 (dd,J=5.0, 17.7 Hz, 1H), 2.82-2.91 (m, 1H), 4.22-4.26 (m, 1H), 5.01-5.06 (m,1H), 5.55 (dd, J=6.8, 16.2 Hz, 1H), 6.23 (dd, J=1.2, 16.2 Hz, 1H),6.91-7.09 (m, 8H).

EXAMPLE 10 ##STR30##

Sodium hydride (content 60%, oil dispersion, 41 mg, 1.01 mmol) waswashed with hexane and suspended in THF (5 ml) under argon atmosphere.To the suspension was added a THF (2 ml) solution of the acetoacetate(0.36 g, 1.0 mmol) obtained in Referential Example 4. The mixture wasstirred for 0.5 hours, cooled to -10° C., and treated with butyllithium(1.52M hexane solution, 0.65 ml, 1.0 mmol). The whole was stirred at-10° C. for 0.5 hours. The resulting dianion was treated with a THF (1ml) solution of the N-methyl-N-methoxyamide (0.37 g, 1.0 mmol) obtainedin Referential Example 6. After stirring at -10° C. for 2 hours and atroom temperature overnight, the mixture was cooled to 0° C., treatedwith 1M hydrochloric acid (0.5 ml) to terminate the reaction, anddiluted with ethyl acetate (25 ml). The organic layer was washed withwater (20 ml×twice) and saturated sodium chloride aq solution and thendried over anhydrous magnesium sulfate. Removal of the solvent in vacuoafforded 0.64 g of a crude product which was purified by thin layerchromatography to give 0.26 g (38% yield) of(4R)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(6E)-3,5-dioxo-9-methyl-8-bis(4-fluorophenyl)methylidene-6-decenoate and0.18 g of the starting acetoacetate recovered. The yield of the desiredproduct was calculated to be 75% based on the starting acetoacetateconsumed. R_(f) =0.28 (hexane:dichloromethane=1:1) [α]_(D) ²⁰ =+112.45°(c 1.05, CHCl₃) IR (KBr): 3070, 2975, 2900, 1735, 1605, 1505, 1440,1320, 1225, 1160, 1095, 1020, 840, 785 cm⁻¹.

¹ H NMR (CDCl₃): δ=0.80-2.13 (br m, 11H), 1.00 (s, 3H), 1.33 (s, 3H),1.36 (s, 3H), 2.83-3.23 (m, 1H), 4.07 (d, 1H, J=9 Hz), 4.73 (s, 1H),5.55 (d, J=19.5 Hz, 1H), 5.90 (d, J=16.5 Hz, 1H), 6.80-8.10 (m, 16H).

EXAMPLE 11 ##STR31##

The β,δ-diketocarboxylic acid ester (0.100 g, 0.15 mmol) obtained inExample 10 was dissolved in a solvent mixture of THF (1 ml) and methanol(0.2 ml). Diethylmethoxyborane (16 mg, 22 μl, 0.16 mmol) was addedthereto at -78° C. under argon atmosphere. The mixture was stirred atroom temperature for 10 minutes and then cooled again to -78° C. Sodiumborohydride (19 mg, 0.5 mmol) as added thereto, and the whole wasstirred at -78° C. for 3 hours and at room temperature overnight. Then,acetic acid (2 ml) was added thereto, and the mixture was stirred for 10minutes, diluted with water (10 ml), and extracted with ethyl acetate(20 ml×twice). The organic layer was washed successively with 5M sodiumhydrogen carbonate aq solution and saturated sodium chloride aq solutionand then dried over anhydrous magnesium sulfate. After concentrating invacuo, methanol was added to the residue and then removed under heating.This operation was repeated 5 times to decompose the boron chelatesformed. The residue was purified by thin layer chromatography (silicagel, ethyl acetate:hexane=3:7) to give 76 mg (79% yield) of(4R)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(3R, 5S,6E)-3,5-dihydroxy-9-methyl-8-bis(4-fluorophenyl)methylidene-6-decenoate.R_(f) =0.38 (hexane:ethyl acetate=2:1) [α]_(D) ²⁰ =+84.32° (c 1.25,CHCl₃) IR (CHCl₃): 3575, 2970, 2875, 1725, 1600, 1505, 1460, 1400, 1155,1095, 1015, 1000, 835 cm⁻¹.

¹ H NMR (CDCl₃): δ=0.79-0.98 (m, 2H), 1.01 (s, 3H), 1.05 (d, J=5.8 Hz,3H), 1.07 (d, J=5.8 Hz, 3H), 1.26 (s, 3H), 1.32 (s, 3H), 1.45-1.54 (m,1H), 1.57-1.61 (m, 4H), 1.72-1.85 (m, 2H), 1.92-2.00 (m, 2H), 2.77-2.85(m, 1H), 2.95-2.99 (m, 1H), 3.82-3.86 (m, 1H), 4.08 (d, J=8.8 Hz, 1H),5.38 (dd, J=6.4, 16.2 Hz, 1H), 5.51 (d, J=8.8 Hz, 1H), 6.04 (dd, J=1.1,16.2 Hz, 1H), 6.86 (m, 8H), 7.38-8.05 (m, 7H). MS:m/z (rel. intensity)678 (M⁺, trace), 269 (14 ), 264 (22), 263 (100), 207 (52), 193 (12), 179(15), 170 (35), 165 (12), 155 (14), 141 (57), 109 (27), 95 (14), 69(15), 43 (41).

REFERENTIAL EXAMPLE 8 ##STR32##

Aqueous 1M sodium hydroxide solution (0.16 ml, 0.16 mmol) was added to amethanol (2 ml) solution of the β,δ-syn-dihydroxycarboxylic acid ester(55 mg, 0.081 mmol) obtained in Example 11, and the whole was stirred atroom temperature for 29 hours. The mixture was diluted with water (5 ml)and extracted with diethyl ether (5 ml×twice) to remove neutralsubstances. The aqueous layer was neutralized with 1M hydrochloric acid(1 ml) and extracted with diethyl ether (15 ml×3 times). The ethereallayer was washed with saturated sodium chloride aq solution, dried overanhydrous magnesium sulfate, and finally concentrated in vacuo. Theresulting crude carboxylic acid was dissolved in toluene (3 ml), and thewhole was heated at 110° C. for 5 hours under argon atmosphere.Concentration in vacuo followed by purification by thin layerchromatography (silica gel, ethyl acetate:hexane=3:7) gave 21 mg (65%yield) of (3R, 5S,6E)-3,5-dihydroxy-9-methyl-8-bis(4-fluorophenyl)methylidene-6-decen-1,5-olide.This product was found to be a mixture of trans-isomer and cis-isomer ina ratio of 79:21. Purification by thin layer chromatography(dichloromethane:acetone=4:1) afforded the pure trans-isomer. HPLCanalysis of the product showed an optical purity of 64% ee. R_(f) =0.36(dichloromethane:acetone=10:1) [α]_(D) ²⁰ =+113.4° (c 0.67, CHCl₃) IR(CHCl₃): 3625, 2950, 2925, 1725, 1600, 1500, 1400, 1360, 1230, 1155,1090, 1060, 1035, 970, 835 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.09 (d, J=5.4 Hz, 3H), 1.11 (d, J=5.4 Hz, 3H),1.46-1.65 (m, 1H), 1.75-1.81 (m, 1H), 2.54-2.61 (m, 1H), 2.70 (dd,J=5.0, 1.77 Hz, 1H), 2.82-2.91 (m, 1H), 4.22-4.26 (m, 1H), 5.01-5.06 (m,1H), 5.55 (dd, J=6.8, 16.2 Hz, 1H), 6.23 (dd, J=1.2, 16.2 Hz, 1H),6.91-7.09 (m, 8H).

EXAMPLE 12 ##STR33##

Following a procedure analogous to Example 1, a THF (5 ml) solution ofthe acetoacetate (1.09 g, 3.0 mmol) obtained in Referential Example 2was allowed to react with a THF (15 ml) suspension of sodium hydride(132 mg, content 60%, oil dispersion, 3.3 mmol) and a hexane solution ofbutyllithium (1.55M, 2.0 ml, 3.1 mmol) successively. The resultingdianion was then treated withN-methoxy-N-methyl-(E)-3-(4-methylphenyl)propenamide (0.62 g, 3.0 mmol)to give 0.49 g (32% yield) of(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(E)-7-(4-methylphenyl)-3,5-dioxo-6-heptenoate together with 0.53 g ofthe starting acetoacetate recovered. The yield of the desired productwas calculated to be 62% based on the starting material consumed. R_(f)=0.17 (hexane:dichloromethane=1:1) [α]_(D) ²⁰ =-145.36° (c 0.63, CHCl₃)IR (CHCl₃): 2925, 2850, 1720, 1625, 1570, 1500, 1475, 1425, 1325, 1245,1150, 1115, 1075, 1005, 960, 800 cm⁻¹.

¹ H NMR (CDCl₃): δ=0.80-2.1 (br m, 5H), 1.00 (s, 3H), 1.22 (s, 3H), 1.30(s, 3H), 2.40 (s, 3H), 2.63 (s, 2H), 4.08 (d, J=9 Hz, 1H), 4.80 (s, 1H),5.58 (d, J=9 Hz, 1H), 6.22 (d, J=15 Hz, 1H), 7.13-8.13 (m, 12H). MS:m/z(rel. intensity) 508 (M⁺, 7), 398 (2), 280 (4), 262 (11), 229 (44), 187(62), 170 (100), 169 (13), 165 (12), 145 (45), 142 (13), 141 (27), 115(15), 41 (13).

EXAMPLE 13 ##STR34##

A toluene solution of diisobutylaluminium hydride (1.02M solution, 0.70ml, 0.72 mmol) was added at -78° C. to a THF (1.5 ml) solution of theβ,δ-diketocarboxylic acid ester (0.173 g, 0.34 mmol) obtained in Example12 and the whole was stirred for 4 hours. After workup of the mixturesimilar to Example 3, the resulting crude product was purified by thinlayer chromatography (silica gel, ethyl acetate:hexane=1:4) to give0.135 g (78% yield) of(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(3S, 6E)-3-hydroxy-5-oxo-7-(4-methylphenyl)-6-heptenoate. R_(f) =0.36(hexane:ethyl acetate=3:1) [α]_(D) ²⁰ =-108.90° (c 1.50, CHCl₃)

HPLC analysis (silica gel 60, hexane:ethanol=80:1) of the product showedthat its diastereomer ratio was 95.5:4.5. The isomer shown in the abovescheme was obtained as main product. IR (CHCl₃): 3560, 2940, 2860, 1720,1670, 1640, 1595, 1560, 1500, 1480, 1455, 1435, 1385, 1320, 1255, 1175,1080, 1010, 970, 790 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.80-2.23 (m, 10H), 1.00 (s, 3H), 1.23 (s, 3H), 1.33(s, 3H), 2.40 (s, 3H), 3.40-3.76 (m, 1H), 4.10 (d, J=9 Hz, 1H), 5.57 (d,J=9 Hz, 1H), 6.50 (d, J=15.75 Hz, 1H), 7.16-8.13 (m, 12H). MS:m/z (rel.intensity) 510 (M⁺, 1), 492 (1), 262 (14), 240 (26), 231 (19), 213 (22),179 (10), 171 (13), 170 (100), 169 (11), 165 (15), 145 (92), 141 (29),117 (17), 115 (20), 91 (13), 71 (13), 43 (21).

EXAMPLE 14 ##STR35##

The β-hydroxy-δ-ketocarboxylic acid ester (49 mg, 0.10 mmol) obtained inExample 13 in a solvent mixture of THF (1 ml) and methanol (0.2 ml) wasallowed to react with diethylmethoxyborane (13 μl, 9.6 mg, 0.10 mmol)and sodium borohydride (8 mg, 0.21 mmol), successively, as described inExample 4. Workup and purification by thin layer chromatography (silicagel, ethyl acetate:hexane=3:7) afforded 40 mg (81% yield) of(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(3S, 5R, 6E)-3,5-dihydroxy-7-(4-methylphenyl)-6-heptenoate. R_(f) =0.31(hexane:ethyl acetate=2:1) [α]_(D) ²⁰ =-87.0° (c 3.00, CHCl₃)

HPLC analysis (silica gel 60, hexane:ethanol=40:1) of the productconfirmed that it was composed of a single diastereomer. IR (CHCl₃):3550, 3460, 2940, 2860, 1720, 1595, 1505, 1480, 1390, 1250, 1175, 1150,1080, 1010, 960, 845, 790, 780 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.01 (s, 3H), 1.08-1.22 (m, 2H), 1.27 (s, 3H), 1.33(s, 3H), 1.45-1.53 (m, 1H), 1.57-1.68 (m, 3H), 1.73-1.84 (m, 2H),1.88-2.01 (m, 3H), 2.33 (s, 3H), 3.07-3.13 (m, 1H), 4.09 (d, J=8.8 Hz,1H), 4.12-4.16 (m, 1H), 5.53 (d, J=8.8 Hz, 1H), 5.95 (dd, J=6.3, 15.9Hz, 1H), 6.47 (d, J=15.9 Hz, 1H), 7.12 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0Hz, 2H), 7.41-7.53 (m, 3H), 7.65 (d, J=7.4 Hz, 1H) 7.73 (d, J=8.2 Hz,1H), 7.87 (dd, J=1.2, 8.0 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H). MS:m/z (rel.intensity) 512 (M⁺, 1), 264 (16), 263 (68), 262 (16), 249 (31), 231(23), 215 (17), 207 (41), 197 (16), 193 (13), 181 (14), 179 (22), 173(14), 171 (16), 170 (100), 169 (28), 167 (14), 165 (23), 155 (35), 145(43), 142 (16), 141 (73), 131 (24), 129 (35), 128 (15), 124 (14), 109(23), 105 (37), 95 (20), 91 (17), 71 (20), 69 (17), 55 (17): 43 (22), 41(32).

REFERENTIAL EXAMPLE 9 ##STR36##

Following a procedure analogous to Referential Example 3, theβ,δ-syn-dihydroxycarboxylic acid ester (30 mg, 0.06 mmol) obtained inExample 14 was hydrolyzed with methanol (2 ml)-1M sodium hydroxide aqsolution (0.15 ml) at room temperature over a period of 45 hours. Afterworkup as before, the resulting carboxylic acid was dissolved in toluene(3 ml), and the whole was heated at 110° C. for 5 hours to lactonize theacid. Purification by thin layer chromatography afforded 8.2 mg (60%yield) of (3S, 5R,6E)-3,5-dihydroxy-7-(4-methylphenyl)-6-hepten-1,5-olide. HPLC analysis(CHIRAL OA and CHIRAL AD column) of the product showed an optical purityof 92% ee. R_(f) =0.32 (dichloromethane:acetone=10:1) [α]_(D) ²⁰ =-5.69°(c 0.65, CHCl₃) mp=126°-127° C. IR (KBr): 3400, 2925, 2850, 1695, 1515,1380, 1315, 1245, 1165, 1065, 1035, 975, 875, 800 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.93-2.00 (m, 1H), 2.08-2.15 (m, 1H), 2.34 (s, 3H),2.64-2.70 (m, 1H), 2.80 (dd, J=5.0, 17.7 Hz, 1H), 4.42-4.46 (m, 1H),5.33-5.38 (m, 1H), 6.15 (dd, J=6.5, 15.9 Hz, 1H), 6.67 (d, J=15.9 Hz,1H), 7.13 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H). MS:m/z (rel.intensity) 232 (M⁺, 19), 214 (6), 145 (17), 144 (14), 131 (18), 129(40), 128 (20), 119 (17), 118 (100), 117 (19), 115 (17), 105 (43), 91(21), 44 (22), 43 (38).

EXAMPLE 15 ##STR37##

The optically active diketocarboxylic acid ester (100 mg, 0.20 mmol)obtained in Example 1 was dissolved in a solvent mixture of THF (2.0 ml)and methanol (0.5 ml). Then, dimethylbromoborane (25 μl, 0.22 mmol) wasadded thereto at -78° C. under argon atmosphere. The mixture was stirredat room temperature for 15 minutes and then cooled again to -78° C.Thereto was added sodium borohydride (38 mg, 1.0 mmol). After stirringat -78° C. for 4 hours, the mixture was gradually warmed to roomtemperature and stirred for 8 hours. Then, acetic acid (0.5 ml) wasadded to terminate the reaction, and the mixture was diluted withdiethyl ether, washed with 5% sodium hydrogen carbonate aq solution (ca.20 ml), and then dried over anhydrous magnesium sulfate. The organiclayer was concentrated in vacuo to give a crude product. Methanol (10ml) was added to the product and then removed in vacuo. This operationwas repeated 10 times to decompose and evaporate organoboron compounds.The resulting crude product was purified by column chromatography(silica gel, hexane:ethyl acetate=4:1) to give 95 mg (95% yield) of(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(3R, 5S, 6E)-7-phenyl-3,5-dihydroxy-6-heptenoate. R_(f) =0.27(hexane:ethyl acetate=2:1) IR (CHCl₃): 3550, 2950, 1730, 1600, 1400,1210, 1095 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.01 (s, 3H), 1.26 (s, 3H), 1.33 (s, 3H), 1.03-1.98(br m, 11H), 2.26-2.57 (m, 1H), 3.05-3.45 (m, 1H), 4.07-4.27 (m, 2H),5.56 (d, J=9.0 Hz, 1H), 6.01 (dd, J=6.0, 16 Hz, 1H), 6.50 (d, J=16 Hz,1H), 7.21-7.53 (m, 8H), 7.64 (d, J=7.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H),7.83 (d, J=8.0 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H). MS:m/z (rel. intensity)498 (M⁺, 3), 480 (M⁺ -H₂ O), 463 (M⁺ -2H₂ O, 5), 263 (79), 170 (100),141 (84). [α]_(D) ²⁰ =-109.1° (c 1.03, CHCl₃)

EXAMPLE 16 ##STR38##

The same product (90 mg, 90% yield) of Example 15 was obtained accordingto the procedure of Example 15 when dimethylethoxyborane (34 μl, 0.22mmol) was used instead of dimethylbromoborane. [α]_(D) ²⁰ =-109.1° (c1.01, CHCl₃)

Other spectral data of the product were identical with those of theproduct obtained in Example 15.

REFERENTIAL EXAMPLE 10 ##STR39##

Following the procedure described in Referential Example 3, theβ,δ-syn-dihydroxycarboxylic acid ester (80 mg, 0.16 mmol) obtained inExample 15 was converted into (3R,5S,6E)-3,5dihydroxy-7-phenyl-6-hepten-1,5-olide (15 mg, 43% yield). HPLC analysis(CHIRAL OA column, hexane:isopropyl alcohol=9:1) of the product showedthat a cis:trans ratio of 24:76 and an optical purity of 42% ee. [α]_(D)²⁰ =+2.66° (c 0.30, CHCl₃)

The other spectral data of the product were identical with those of theproduct obtained in Referential Example 3.

REFERENTIAL EXAMPLE 11 ##STR40##

Butyllithium (1.64M hexane solution, 7.54 ml, 12.4 mmol) was added to aTHF (40 ml) solution of diisopropylamine (1.25 g, 12.4 mmol) at -78° C.and the mixture was stirred for 15 minutes. Thereto was added a THF (20ml) solution of N-methoxy-N-methylacetamide (1.27 g, 12.3 mmol) at -78°C., and the resulting mixture was stirred at -78° C. for 15 minutes. Tothis mixture was added a THF (40 ml) solution of2-cyclopropyl-4-(4-fluorophenyl)-3-formylquinoline (3.00 g, 10.3 mmol).The reaction mixture was stirred at -78° C. to room temperature over aperiod of 3 hours before quenching with water and extraction withdiethyl ether. The ethereal organic layer was washed with saturatedsodium chloride aq solution, dried over magnesium sulfate, andconcentrated in vacuo. The residue was purified by column chromatography(hexane:ethyl acetate=2:1) to give N-methoxy-N-methyl-3-{2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl}-3-hydroxypropanamide (3.70 g, 91%yield). R_(f) =0.30 (hexane:ethyl acetate=2:1) IR (CHCl₃): 3450, 3000,1640, 1515, 1490, 1420, 1230, 1070, 780 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.02-1.16 (m, 3H), 1.74-1.79 (m, 1H), 2.66 (d, J=17.2Hz, 1H), 3.17 (s, 3H), 3.16-3.24 (m, 1H), 3.52 (dd, J=17.2, 11.3 Hz,1H), 3.62 (s, 3H), 4.14 (d, J=2.4 Hz, 1H), 5.35 (dt, J=11.3, 2.4 Hz,1H), 7.12-7.35 (m, 6H), 7.58 (dd, J=6.8, 1.4 Hz, 1H), 7.92 (dq, J=8.4,0.6 Hz, 1H). MS:m/z (rel. intensity) 394 (M⁺, 11), 363, (M⁺,-OMe, 46),334 (58), 292 (100), 274 (38), 263 (37).

A dichloromethane (10 ml) solution of methanesulfonyl chloride (1.44 g,12.6 mmol) was added to a dichloromethane (40 ml) solution ofN-methoxy-N-methyl-3-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3-hydroxypropanamide(3.30 g, 8.38 mmol) and triethylamine (1.27 g, 12.6 mmol). The resultingmixture was stirred at 0° C. for 30 minutes and at room temperature for3 hours before treatment with triethylamine (1.27 g, 12.6 mmol). Themixture was heated to reflux for 3 hours, quenched with saturated NaHCO₃aq solution, and extracted with dichloromethane. The organic layer waswashed with saturated NaCl aq solution, dried over magnesium sulfate,and then concentrated. The residue was purified by column chromatography(hexane:ethyl acetate=3:1) to giveN-methoxy-N-methyl-(E)-3-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}propenamide(2.52 g, 80% yield). mp=141° C. R_(f) =0.52 (hexane:ethyl acetate=2:1)IR (CHCl₃): 3000, 1650, 1610, 1515, 1490, 1415, 1385, 1220, 1090, 1025,840, 760 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.05-1.09 (m, 2H), 1.37-1.40 (m, 2H), 2.40 (m, 1H),3.21 (s, 3H), 3.49 (s, 3H), 6.46 (d, J=16.1 Hz, 1H), 7.16-7.27 (m, 4H),7.30-7.37 (m, 2H), 7.62 (dd, J=6.2, 2.0 Hz, 1H), 7.89 (d, J=16.1 Hz,1H), 7.96 (d, J=8.2 Hz, 1H). MS: m/z (rel. intensity) 376 (M⁺, 9), 316(48), 288 (51), 260 (12), 185 (14), 129 (11), 43 (100).

EXAMPLE 17 ##STR41##

To a THF (20 ml) suspension of sodium hydride (60% in oil, 0.26 g, 6.50mmol) was added a THF (30 ml) solution of (4 S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan2-exo-ylacetoacetate (2.37 g, 6.50 mmol) at 0° C., and the mixture was stirredfor 15 min. To this mixture was added butyllithium (1.64 M hexanesolution, 4.00 ml, 6.55 mmol) at 0° C., and the resulting mixture wascooled to -78° C. Thereto was added a THF (50 ml) solution ofN-methoxy-N-methyl-(E)-3-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}propenamide(2.45 g, 6.51 mmol) as obtained in Example 16. The mixture was stirredat -78° C. to 0° C. over 3 hours before hydrolysis with 1M hydrochloricacid (20 ml), neutralization with saturated sodium hydrogen carbonate aqsolution and extraction with ether. The organic layer was washed withsaturated sodium chloride aq solution, dried over magnesium sulfate, andconcentrated in vacuo. The residue was purified by column chromatography(hexane:ethyl acetate=15:1) to give(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(E)-7-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3,5-dioxo-6-heptenoate (2.12 g, 48%yield). Meantime the starting materials(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-ylacetoacetate (0.60 g, 25%) andN-methoxy-N-methyl-(E)-3-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}propenamide(1.22 g, 50%) were recovered. R_(f) =0.48 (hexane:ethyl acetate=5:1)[α]_(D) ²⁰ =-106.60° (c 1.03, CHCl₃) IR (CHCl₃): 2960, 1730, 1605, 1515,1490, 1395, 1235, 1090, 1030 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.00 (s, 3H), 1.12 (dd, J=8.9, 3.0 Hz, 2H), 1.22 (s,3H), 1.24 (s, 3H), 1.42-1.60 (m, 4H), 1.72-1.79 (m, 1H), 1.91-1.99 (m,2H), 2.41 (m, 1H), 2.52 (d, J=14.8 Hz, 1H), 2.57 (d, J=14.8 Hz, 1H),4.05 (d, J=8.7 Hz, 1H), 4.69 (s, 1H), 5.87 (d, J=16.2 Hz, 1H), 7.20-7.47(m, 10H), 7.56 (m, 3H), 7.72 (dd, J=8.0, 1.1 Hz, 1H), 7.98 (d, J=8.4 Hz,1H), 8.00 (d, J=8.4 Hz, 1H). MS: m/z (rel. intensity) 679 (M⁺, 0.5), 401(3 ), 399 (32), 356 (8), 288 (50), 274 (22), 170 (100).

EXAMPLE 18 ##STR42##

The diketocarboxylic acid ester (200 mg, 0.29 mmol) obtained in Example17 was dissolved into a solvent mixture of THF (2.0 ml) and methanol(0.5 ml). Then, diethylmethoxyborane (32 mg, 0.32 mmol) was addedthereto at -78° C. under argon atmosphere. The mixture was once warmedto room temperature under stirring over 15 minutes and then cooled againto -78° C. Thereto was added sodium borohydride (56 mg, 1.48 mmol).After stirring at -78° C. for 4 hours and at -78° C. to room temperatureover 8 hours, the mixture was treated with acetic acid (0.5 ml) toterminate the reaction, poured into saturated sodium hydrogen carbonateaq solution and then extracted with diethyl ether. The organic layer waswashed with saturated sodium chloride aq solution, dried over magnesiumsulfate, and concentrated in vacuo. Methanol (10 ml) was added todissolve the residue and then removed in vacuo. This operation wasrepeated 10 times to decompose and evaporate organoboron compounds. Theresulting crude product was purified by column chromatography(hexane:ethyl acetate=15:1) to give(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(3S,5R,6E)-7-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3,5-dihydroxy-6-heptenoate(181 mg, 90% yield). R_(f) =0.36 (hexane:AcOEt=2:1) [α]_(D) ²⁰ =-72.19°(c 1.00, CHCl₃) IR (CHCl₃): 3460, 3010, 2960, 1725, 1605, 1515, 1490,1400, 1220, 1090, 790 cm⁻¹.

¹ H NMR (CDCl₃): δ=0.80 (d, J=14.3 Hz, 1H), 0.88-0.96 (m, 1H), 1.02 (s,3H), 1.00-1.05 (m, 2H), 1.27 (s, 3H), 1.33 (s, 3H), 1.31-1.37 (m, 2H),1.46-1.55 (m, 1H), 1.57-1.63 (m, 2H), 1.75-1.82 (m, 1H), 1.83 (dd,J=15.4, 9.4 Hz, 1H), 1.92-1.98 (m, 1H), 2.00 (d, J= 4.8 Hz, 1H), 2.39(m, 1H), 2.92-2.99 (m, 1H), 3.03 (d, J=1.4 Hz, 1H), 3.95-3.99 (m, 1H),4.08 (d, J=8.5 Hz, 1H), 5.40 (dd, J=16.2, 5.8 Hz, 1H), 5.52 (d, J=8.5Hz, 1H), 6.50 (dd, J=16.2, 1.4 Hz, 1H), 7.07-7.18 (m, 4H), 7.27-7.34 (m,2H), 7.38-7.44 (m, 2H), 7.50 (dd, J=7.0, 1.5 Hz, 1H), 7.58 (dd, J=6.3,2.0 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.80 (dd,J=8.0, 1.2 Hz, 1H), 7.94 (d, J=7.7 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H). MS:m/z (rel. intensity) 683 (M⁺, 2), 644 (1), 420 (14), 288 (53), 275 (34),170 (100).

REFERENTIAL EXAMPLE 12 ##STR43##

Aqueous 1M sodium hydroxide solution (0.5 ml) was added to a methanol(5.0 ml) solution of the dihydroxyester (70 mg, 0.10 mmol) obtained inExample 18. The mixture was stirred at room temperature for 12 hours.Then, the resulting mixture was poured into sodium acetate-acetic acidbuffer (15 ml, pH=4-5) and extracted with ethyl acetate. The organiclayer was washed with saturated sodium chloride aq solution, dried overanhydrous magnesium sulfate, and concentrated in vacuo. The residue wassubjected to preparative thin layer chromatography (hexane:ethylacetate=1:1) to separate the desired product from(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-ol (26mg, 91%). The desired product was then dissolved in toluene (25 ml), andthe solution was heated under reflux for 12 hours. After removing thetoluene in vacuo, the residue was purified by preparative thin layerchromatography (hexane:ethyl acetate=1:2) to give(3S,5R,6E)-7-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3,5-dihydroxy-6-hepten-1,5-olide (22 mg, 53% yield) ascolorless foam. HPLC analysis (CHIRALPACK AS, hexane:isopropylalcohol=9:1) of the product showed a cis:trans ratio of 77:23 and anoptical purity of 58% ee. R_(f) =0.19 (hexane:AcOEt=2:1) [α]_(D) ²⁰=+14.77° (c 1.57, CHCl₃) IR (CHCl₃): 3440, 3005, 1730, 1600, 1560, 1510,1490, 1410, 1230, 1155, 1060, 970, 830, 730 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.03-1.08 (m, 2H), 1.30-1.40 (m, 2H), 1.56-1.60 (m,1H), 1.78 (m, 1H), 2.38 (m, 1H), 2.60 (ddd, J=7.4, 4.0, 1.5 Hz, 1H),2.70 (dd, J=13.0, 4.8 Hz, 1H), 4.25 (m, 1H), 5.18 and 4.66 (m, 1H, ratio77:23), 5.62 (dd, J=16.1, 6.2 Hz, 1H), 6.72 (dd, J=16.1, 1.4 Hz, 1H),7.17-7.25 (m, 4H), 7.30-7.37 (m, 2H), 7.61 (dd, J=6.1, 2.1 Hz, 1H), 7.96(d, J=8.3 Hz, 1H). MS: m/z (rel. intensity) 403 (M⁺, 9), 316 (11), 288(100), 274 (12).

EXAMPLE 19 ##STR44##

The diketocarboxylic acid ester (200 mg, 0.29 mmol) obtained in Example17 was dissolved in THF (5.0 ml). Diisobutylaluminium hydride (0.70 ml,1.00M in hexane, 0.70 mmol) was added thereto at -90° C. under argonatmosphere, and the whole was stirred at -90° C. for 24 hours. To themixture was added saturated Na₂ SO₄ aq solution (0.1 ml) to terminatethe reaction. The resulting mixture was diluted with ethyl acetate (20ml), dried over anhydrous magnesium sulfate and then concentrated invacuo. The crude product was purified by column chromatography(hexane:ethyl acetate=4:1) to give(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(3S,6E)-7-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3-hydroxy-5-oxo-6-heptenoate(111 mg, 56% yield). R_(f) =0.13 (hexane:AcOEt=5:1) [α]_(D) ²⁰ =-77.75°(C 0.98 , CHCl₃) IR (CHCl₃): 2950, 1720, 1600, 1550, 1510, 1490, 1390,1230, 1210, 1090, 1030 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.01 (s, 3H), 1.06 (m, 2H), 1.24 (s, 3H), 1.33 (s,3H), 1.39-1.42 (m, 2H), 1.48-1.62 (m, 2H), 1.72-2.04 (m, 7H), 2.30 (m,1H), 3.47-3.55 (m, 1H), 4.08 (d, J=8.7 Hz, 1H), 5.53 (d, J=8.7 Hz, 1H),6.15 (d, J=16.5 Hz, 1H), 7.17-7.21 (m, 4H), 7.32-7.47 (m, 5H), 7.48 (d,J=16.5 Hz, 1H), 7.63-7.77 (m, 3H), 7.77 (dd, J=8.0, 1.2 Hz, 1H), 7.97(d, J=8.4 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H). MS: m/z (rel. intensity) 681(M⁺, 0.6), 663 (M+-H₂ O, 1), 402 (15), 384 (12), 350 (8), 331 (11), 316(13), 288 (79), 240 (31), 170 (100).

EXAMPLE 20 ##STR45##

The hydroxycarboxylic acid ester (102 mg, 0.15 mmol) obtained in Example19 was dissolved in a solvent mixture of THF (2.0 ml) and methanol (0.5ml). Diethylmethoxyborane (16 mg, 0.16 mmol) was added thereto at -78°C. under argon atmosphere. The mixture was stirred at -78° C. to roomtemperature over 15 minutes and cooled again at -78° C. Sodiumborohydride (28 mg, 0.74 mmol) was added thereto. After stirring at -78°C. for 4 hours and at -78° C. to room temperature over 8 hours, themixture was treated with acetic acid (0.5 ml) to quench the reaction,poured into saturated sodium hydrogen carbonate aq solution and finallyextracted with diethyl ether. The organic layer was washed withsaturated sodium chloride aq solution, dried over anhydrous magnesiumsulfate and then concentrated in vacuo. Methanol (10 ml) was added todissolve the residue and then removed in vacuo. This operation wasrepeated 10 times to decompose and evaporate organoboron compounds. Theresulting crude product was purified by column chromatography(hexane:ethyl acetate=15:1) to give(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-yl(3S,5R,6E)-7-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3,5-dihydroxy-6-heptenoate(87 mg, 85% yield) R_(f) =0.36 (hexane:AcOEt=2:1) [α]_(D) ²⁰ =-73.78° (c1.03, CHCl₃) IR (CHCl₃): 3460, 3010, 2960, 1725, 1605, 1515, 1490, 1400,1220, 1090, 790 cm⁻¹.

¹ H NMR (CDCl₃): δ=0.80 (d, J=14.3 Hz, 1H), 0.88-0.96 (m, 1H), 1.02 (s,3H), 1.00-1.05 (m, 2H), 1.27 (s, 3H), 1.33 (s, 3H), 1.31-1.37 (m, 2H),1.46-1.55 (m, 1H), 1.57-1.63 (m, 2H), 1.75-1.82 (m, 1H), 1.83 (dd,J=15.4, 9.4 Hz, 1H), 1.92-1.98 (m, 1H), 2.00 (d, J=4.8 Hz, 1H), 2.39 (m,1H), 2.92-2.99 (m, 1H), 3.03 (d, J=1.4 Hz, 1H), 3.95-3.99 (m, 1H), 4.08(d, J=8.5 Hz, 1H), 5.40 (dd, J=16.2, 5.8 Hz, 1H), 5.52 (d, J=8.5 Hz,1H), 6.50 (dd, J=16.2, 1.4 Hz, 1H), 7.07-7.18 (m, 4H), 7.27-7.34 (m,2H), 7.38-7.44 (m, 2H), 7.50 (dd, J=7.0, 1.5 Hz, 1H), 7.58 (dd, J=6.3,2.0 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7 80 (dd,J=8.0, 1.2 Hz, 1H), 7 94 (d, J=7.7 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H). MS:m/z (rel intensity) 683 (M⁺, 1) 665 (M+-H₂ O, 0.3) 644 (1), 420 (16),288 (53), 275 (34), 170 (100).

REFERENTIAL EXAMPLE 13 ##STR46##

Aqueous 1M sodium hydroxide solution (0.5 ml, 0.10 mmol) was added to amethanol (5.0 ml) solution of the dihydroxyester (60 mg, 0.09 mmol)obtained in Example 20. The mixture was stirred at room temperature for12 hours. Then, the resulting mixture was poured into sodiumacetate-acetic acid buffer (15 ml, pH=4-5) and extracted with ethylacetate. The organic layer was washed with saturated sodium chloride aqsolution, dried over anhydrous magnesium sulfate, and concentrated invacuo. The residue was subjected to preparative thin layerchromatography (hexane:ethyl acetate=1:1) to separate the desiredproduct from(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-ol (22mg, 90%). The desired product was then dissolved in toluene (25 ml), andthe solution was heated under reflux for 12 hours. After removing thetoluene in vacuo, the residue was purified by preparative thin layerchromatography (hexane:ethyl acetate=1:2) to give (3S,5R,6E)-7-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3,5-dihydroxy-6-hepten-1,5-olide(16 mg, 45% yield) as colorless foam. HPLC analysis (CHIRALPACK AS,hexane:isopropyl alcohol=9:1) of the product showed a cis:trans ratio of96:4 and an optical purity of 93% ee. R_(f) =0.19 (hexane:AcOEt=2:1)[α]_(D) ²⁰ =+6.98° (c 1.74, CHCl₃) IR (CHCl₃): 3440, 3005, 1730, 1600,1560, 1510, 1490, 1410, 1230, 1155, 1060, 970, 830, 730 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.03-1.08 (m, 2H), 1.30-1.40 (m, 2H), 1.56-1.60 (m,1H), 1.78 (m, 1H), 2.38 (m, 1H), 2.60 (ddd, J=7.4, 4.0, 1.5 Hz, 1H),2.70 (dd, J=13.0, 4.8 Hz, 1H), 4.25 (m, 1H), 5.18 (m, 1H), 5.62 (dd,J=16.1, 6.2 Hz, 1H), 6.72 (dd, J=16.1, 1.4 Hz, 1H), 7.17-7.25 (m, 4H),7.30-7.37 (m, 2H), 7.61 (dd, J=6.1, 2.1 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H).MS: m/z (rel. intensity) 403 (M⁺, 9), 316 (11), 288 (100), 274 (12).

EXAMPLE 21 ##STR47##

The diketocarboxylic acid ester (100 mg, 0.15 mmol) obtained in Example17 was dissolved in a solvent mixture of THF (2.0 ml) and methanol (0.5ml). Dimethylethoxyborane (14 mg, 0.16 mmol) was added thereto at -78°C., and the whole was stirred for 15 minutes. Thereto was added sodiumborohydride (28 mg, 0.74 mmol). After stirring at -78° C. for 4 hoursand at -78° C. to room temperature over 8 hours, the mixture was treatedwith acetic acid (0.5 ml) to terminate the reaction, poured intosaturated sodium hydrogen carbonate aq solution and then extracted withdiethyl ether. The organic layer was washed with saturated sodiumchloride aq solution, dried over magnesium sulfate, and concentrated invacuo. Methanol (10 ml) was added to dissolve the residue and thenremoved in vacuo. This operation was repeated 10 times to decompose andevaporate organoboron compounds. The resulting crude product waspurified by column chromatography (hexane:ethyl acetate=3:1) to give(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)-bicyclo[2.2.1]heptan-2-exo-yl(3R,5S,6E)-7-{2-cyclopropyl-4(4-fluorophenyl)quinolin-3-yl}-3,5-dihydroxy-6-heptenoate(95 mg, 94% yield). R_(f) =0.36 (hexane:AcOEt=2:1) [α]_(D) ²⁰ =-75.29°(C 1.02, CHCl₃) IR (CHCl₃): 3460, 3010, 2960, 1725, 1605, 1515, 1490,1400, 1220, 1090, 790 cm⁻¹.

¹ H NMR (CDCl₃): δ=0.75-0.96 (m, 2H), 1.02 (s, 3H), 1.00-1.05 (m, 2H),1.27 and 1.26 (s, 3H), 1.33 and 1.32 (s, 3H), 1.31-1.37 (m, 2H),1.46-1.55 (m, 1H), 1.57-1.63 (m, 2H), 1.75-1.98 (m, 3H), 2.00 (br s,1H), 2.39 (m, 1H), 2.92-2.99 (m, 1H), 3.09 and 3.17 (m, 1H), 3.95-3.99(m, 1H), 4.08 (br d, J=8.5 Hz, 1H), 5.36-5.47 (m, 1H), 5.51-5.58 (m,1H), 6.50 and 6.51 (dd, J=16.2, 1.4 Hz, 1H), 7.07-7.18 (m, 4H),7.27-7.34 (m, 2H), 7.38-7.52 (m, 3H), 7.55-7.83 (m, 4H), 7.94 (m, 1H),8.04 (m, 1H). MS: m/z (rel. intensity) 683 (M⁺, 12), 642 (0.3), 420(41), (13), 288 (78), 275 (34), 263 (100), 207 (74), 170 (93).

REFERENTIAL EXAMPLE 14 ##STR48##

Aqueous 1M sodium hydroxide solution (0.5 ml) was added to a methanol(5.0 ml) solution of the dihydroxyester (90 mg, 0.13 mmol) obtained inExample 21. The mixture was stirred at room temperature for 12 hours.Then, the resulting mixture was poured into sodium acetate-acetic acidbuffer (15 ml, pH=4-5) and extracted with ethyl acetate. The organiclayer was washed with saturated sodium chloride aq solution, dried overanhydrous magnesium sulfate, and concentrated in vacuo. The residue wassubjected to preparative thin layer chromatography (hexane:ethylacetate=1:1) to separate the desired product from(4S)-4,7,7-trimethyl-3-exo-(1-naphthyl)bicyclo[2.2.1]heptan-2-exo-ol (33mg, 90%). The desired product was then dissolved in toluene (25 ml), andthe solution was heated under reflux for 12 hours. After removing thetoluene in vacuo, the residue was purified by preparative thin layerchromatography (hexane:ethyl acetate=1:2) to give of(3R,5S,6E)-7-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3,5-dihydroxy-6-hepten-1,5-olide (26 mg, 48% yield) as colorlessfoam. HPLC analysis (CHIRALPACK AS, hexane:isopropyl alcohol=9:1) of theproduct showed a cis:trans ratio of 64:36 and an optical purity of 37%ee. R_(f) =0.19 (hexane:AcOEt=2:1) [α]_(D) ²⁰ =-20.90° (c 0.56 CHCl₃) IR(CHCl₃): 3440, 3005, 1730, 1600, 1560, 1510, 1490, 1410, 1230, 1155,1060, 970, 830, 730 cm⁻¹.

¹ H NMR (CDCl₃): δ=1.03-1.08 (m, 2H), 1.30-1.40 (m, 2H), 1.56-1.60 (m,1H), 1.78 (m, 1H), 2.38 (m , 1H), 2.60 (ddd, J=7.4, 4.0, 1.5 Hz, 1H),2.70 (dd, J=13.0, 4.8 Hz, 1H), 4.25 (m, 1H), 5.18 and 4.66 (m, 1H, ratio64:36), 5.62 (dd, J=16.1, 6.2 Hz, 1H), 6.72 (dd, J=16.1, 1.4 Hz, 1H),7.17-7.25 (m, 4H), 7.30-7.37 (m, 2H), 7.61 (dd, J=6.1, 2.1 Hz, 1H), 7.96(d, J=8.3 Hz, 1H). MS: m/z (rel intensity) 403 (M⁺, 9) 316 (11), 288(100) 274 (12)

What is claimed is:
 1. An optically active ester ofβ,δ-syn-dihydroxycarboxylic acid represented by the following formula(IV): ##STR49## wherein R is a phenyl group optionally substituted withone to four substituents selected from the group consisting of a C₁ -C₃alkyl group, a halogen, a C₁ -C₃ alkoxy group, and a phenyl groupoptionally substituted with a halogen, a C₁ -C₃ alkyl group or both ahalogen and C₁ -C₃ alkyl group;a vinyl group substituted with two orthree substituents selected from the group consisting of a C₁ -C₃ alkylgroup, a phenyl group optionally substituted with a halogen, a C₁ -C₃alkyl group or both a halogen and C₁ -C₃ alkyl group, and a1H-tetrazolyl group optionally substituted with a halogen, a C₁ -C₃alkyl group or both a halogen and C₁ -C₃ alkyl group; a pyridyl groupoptionally substituted with one to four substituents selected from thegroup consisting of a halogen, a cyclopropyl group, an oxo group, a C₁-C₃ alkyl group optionally substituted with benzyloxy group, and aphenyl group optionally substituted with a halogen, a C₁ -C₃ alkyl groupor both a halogen and C₁ -C₃ alkyl group; or a pyridyl group condensedwith benzene ring, pyrazole ring, or thiophene ring, optionallysubstituted with one to four substituents selected from the groupconsisting of a halogen, a cyclopropyl group, an oxo group, a C₁ -C₄alkyl group optionally substituted with benzyloxy group, and a phenylgroup optionally substituted with a halogen, a C₁ -C₃ alkyl group orboth a halogen and C₁ -C₃ alkyl group; and Ar is a condensed aromaticgroup, or an enantiomer thereof.
 2. An optically active enantio-ester ofβ,δ-syn-dihydroxycarboxylic acid represented by the following formula(V): ##STR50## wherein R is a phenyl group optionally substituted withone to four substituents selected from the group consisting of a C₁ -C₃alkyl group, a halogen, a C₁ -C₃ alkoxy group, and a phenyl groupoptionally substituted with a halogen, a C₁ -C₃ alkyl group or both ahalogen and C₁ -C₃ alkyl group;a vinyl group substituted with two orthree substituents selected from the group consisting of a C₁ -C₃ alkylgroup, a phenyl group optionally substituted with a halogen, a C₁ -C₃alkyl group or both a halogen and C₁ -C₃ alkyl group, and a1H-tetrazolyl group optionally substituted with a halogen, a C₁ -C₃alkyl group or both a halogen and C₁ -C₃ alkyl group; a pyridyl groupoptionally substituted with one to four substituents selected from thegroup consisting of a halogen, a cyclopropyl group, an oxo group, a C₁-C₃ alkyl group optionally substituted with benzyloxy group, and aphenyl group optionally substituted with a halogen, a C₁ -C₃ alkyl groupor both a halogen and a C₁ -C₃ alkyl group; or a pyridyl group condensedwith benzene ring, pyrazole ring, or thiophene ring, optionallysubstituted with one to four substituents selected from the groupconsisting of a halogen, a cyclopropyl group, an oxo group, a C₁ -C₄alkyl group optionally substituted with benzyloxy group, and a phenylgroup optionally substituted with a halogen, a C₁ -C₃ alkyl group orboth a halogen and C₁ -C₃ alkyl group; and Ar is a condensed aromaticgroup, or an enantiomer thereof.
 3. The ester according to claim 1 or 2wherein Ar is selected from the group consisting of naphthyl group,anthryl group, and phenanthryl group.
 4. The ester according to claim 1or 2 wherein the pyridyl group condensed with benzene ring, pyrazolering or thiophene ring, is selected from the group consisting ofquinolin-3-yl group, pyrazolo[3,4-b]pyridin-5-yl, andthieno[2,3-b]pyridin-5-yl-group.
 5. An ester according to claim 1 or 2,wherein R is a phenyl group; a substituted phenyl selected from thegroup consisting of 4-tolyl, 4-chlorophenyl, 4-methoxyphenyl,3,5-dichloro-6-(4-fluorophenyl)phenyl, and2,4-dimethyl-6-(4-fluoro-3-methylphenyl)phenyl; a substituted pyridylselected from the group consisting of 4-phenyl-2-methylpyridin-3-yl,2-isopropyl-6-phenyl-4-(4-fluoro-phenyl)pyridin-3-yl,2,5-diisopropyl-4-(4-fluorophenyl)-pyridin-3-yl,2,6-diisopropyl-4-(4-fluorophenyl)-5-benzyloxymethylpyridin-3-yl,6-cyclopropyl-4-(4-fluoro-phenyl)-1,3-dimethylpyrazolo[3,4-b]pyridin-5-yl,4-(4-fluorophenyl)-1,3-dimethyl-6-(1-methylethyl)pyrazolo[3,4-b]pyridin-5-yl,1-t-butyl-6-cyclopropyl-4-(4-fluorophenyl)-3-methylpyrazolo[3,4-b]pyridin-5-yl,1-t-butyl-6-cyclopropyl-4-(4-fluorophenyl)-3-phenylpyrazolo[3,4-b]pyridin-5-yl,6-cyclopropyl-4-(4-fluorophenyl)thieno[2,3-b]pyridin-5-yl, and6-cyclopropyl-3-ethyl-4-(4-fluorophenyl)-2-methylthieno[2,3-b]pyridin-5-yl;a substituted quinolyl selected from the group consisting of3-isopropyl-l-(4-fluorophenyl)-4-oxoquinolin-2-yl,2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl,4-(4-fluorophenyl)-2-(1-methylethyl)quinolin-3-yl,6-chloro-2-(1-methylethyl)-4-phenylquinolin-3-yl,4-(4-fluorophenyl)-6-methyl-2-(1-methylethyl)quinolin-3-yl, and2-cyclopropyl-4-(4-fluorophenyl)-8-methylquinolin-3-yl; or a substitutedvinyl selected from the group consisting of 2,2-diphenylethenyl,1-isopropyl-2,2-bis(4-fluorophenyl)ethenyl, and1-(1-methyl-1H-tetrazol-5-yl)-2,2-(4-fluorophenyl)ethenyl.